Fixed dose combination of aspirin and pantoprazole: Results of a multicenter, comparative, randomized, double-blind, double dummy, phase III study in Indian patients

Abstract

Objective

To compare the efficacy and safety of a fixed-dose combination of aspirin and pantoprazole with that of aspirin alone for the prevention of gastro duodenal mucosal damage in patients taking aspirin for secondary prevention of cardiovascular disease or cerebrovascular disease.

Methods

This was a comparative, double-blind, double-dummy, randomized, multicenter, phase III study conducted in patients taking aspirin ≤150 mg daily for ≥3 to ≤6 months and expected to require daily aspirin therapy for at least 6 months for the secondary prevention of cardiovascular disease or cerebrovascular disease.

Results

A total of 240 patients were randomized to receive either a fixed-dose combination of aspirin 150 mg and pantoprazole 20 mg or aspirin 150 mg alone in a 2:1 ratio. The proportion of non-responders (patients experiencing gastroduodenal events) was 9.7 % in the test group (fixed-dose combination of aspirin 150 mg and pantoprazole 20 mg) compared to 19.7 % in the comparator group (aspirin 150 mg) at week 12, while the proportions were 11.0 % in the test group and 22.4 % in the comparator group at the end of 24 weeks of treatment (p-value was <0.05 at week 12 and 24). GI injuries were significantly less in test group as compared to comparator group. Both drugs were well tolerated by all patients.

Conclusion

The fixed-dose combination of aspirin 150 mg and pantoprazole 20 mg was found to be more efficacious and safer compared to aspirin 150 mg alone for the prevention of gastroduodenal mucosal damage in patients receiving aspirin.

1. Introduction

Cardiovascular Diseases (CVDs) such as myocardial infarction and cerebrovascular diseases such as stroke are the leading cause of death which account for 17.7 million deaths.¹ According to world health organization, one-fifth of these deaths worldwide occurs in India especially in younger population. The results of global burden of disease study state age-standardized shows that CVD death rate is 272 per 100000 populations in India which is much higher than that of global death rate of 235.² Indians are known to have highest coronary artery disease (CAD) rates and high mortality rate. According to hospital-based CV morbidity and mortality data, CVDs contributed to 28·1 % of total deaths and 14·1 % of total disability-adjusted life years (DALYs) in India in 2016 as compared to 15·2 % and 6·9 %, respectively in 1990.³ This may not be actual CV disease burden because majority of deaths occurs at home without knowing the cause of death.

Low dose aspirin is extensively used as an antiplatelet agent for the prevention of cardiovascular and cerebrovascular events. Aspirin prevents cardiovascular morbidity and mortality⁴, and significant number of patients above the age of 45 years use it regularly.⁵ Long-term aspirin administration inhibits the platelet aggregation and decrease the vascular deaths among patients with myocardial infarction, stroke and other cardiovascular disease. The American College of Cardiology (ACC) and the American Heart Association (AHA)⁶ has recommended daily aspirin at a dose of at least 75–325 mg for prevention of subsequent complications among patients of cardiovascular disease.

Gastrointestinal (GI) bleeding is the most common side effect in patients taking antiplatelet or anticoagulant drugs.⁷ Epidemiologic data shows that patients who are taking cardio-protective aspirin have a 2-times higher risk of upper GI complications.⁸ Patients who are taking both, vitamin K antagonists and nonsteroidal anti-inflammatory drugs have 12 times higher risk of upper GI complications.⁸ It is very important to prevent GI bleeding and related complications when patient is on antiplatelet therapy since very long time. A meta-analysis of 345 randomized trials including 64905 patients showed that proton pump inhibitors (PPIs) prevent peptic ulcers and decrease the risk of peptic ulcer bleeding due to nonsteroidal anti-inflammatory drugs.⁹ A randomized trial of 2426 patients showed that PPIs prevent the peptic ulcer diagnosed at endoscopy in patients taking aspirin.¹⁰ Another study suggests that PPI therapy prevents GI events in patients taking dual antiplatelet therapy.¹¹

Guidelines by AHA and ACCsuggest that PPIs should be given to patients receiving the antiplatelet therapy to reduce the risk of upper GI bleeding.¹² In line with these guidelines, all the patients receiving the antiplatelet drugs are also prescribed PPIs on a daily dosage regimen in addition to other medications which increases the pill burden. Increased pill count enhances the probability of non-compliance to medications and can lead to more serious complications.¹³ To overcome this, Fixed Dose Combinations (FDCs) of PPI and aspirin has been developed. The present phase III study was planned to compare safety and efficacy of fixed dose combination of aspirin 150 mg and pantoprazole 20 mg to aspirin 150 mg alone for the prevention of gastro duodenal mucosal damage in patients receiving aspirin for secondary prevention of cardiovascular disease or cerebrovascular disease.

2. Methodology

This was a comparative, double-blind, double dummy, randomized, multicenter, phase III study. The study was conducted at 13 tertiary care hospitals geographically spread across the India. The study was carried in compliance with the Indian Good Clinical Practice Guidelines, Ethical Principles of the Declaration of Helsinki, ICMR guidelines for Biomedical Research on Human Subjects (2017) and New Drugs and Clinical Trial Rules, 2019 (CDSCO). The study was approved by the Office of the Drug Controller General of India and was registered with the Clinical Trials Registry of India (www.ctri.nic.in;CTRI/2021/11/037831) before enrollment of first patient.

The study was initiated after review and approval by the Institutional Ethics Committees at each of the 13 participating study centers. Written informed consent was obtained from all patients before initiation of any study related activity.

3. Patients

Patients aged ≥55 years, taking aspirin ≤150 mg daily for ≥3 to ≤6 months and expected to require daily aspirin therapy for at least 6 months for the secondary prevention of cardiovascular disease or cerebrovascular disease (Patients diagnosed with coronary heart disease, peripheral vascular disease or ischemic stroke or transient ischemic attacks and patients with history of coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI) with or without stent, carotid endarterectomy) were included into the study. Patients with 0–10 gastric or duodenum erosion(s) or submucosal hemorrhage(s) (Lanza score 0 to 2)* were enrolled into the study (*Gastro duodenal injury was determined by endoscopic examination. Gastric and duodenal lesions were scored using the Lanza (1988) method).

Key exclusion criteria were: Patients with concurrent erosive or ulcerative esophagitis, esophageal stricture, severe esophagitis, long-segment Barrett's esophagus, history of serious upper gastro-intestinal events such as perforation, or obstruction, pyloric stenosis, previous gastric or duodenal surgery, known hypersensitivity or intolerance to aspirin, pantoprazole or related class of drugs or any of the excipients of investigational product, positive test result for H. pylori, with revascularization procedure (i.e., CABG, Percutaneous Transluminal Coronary Angioplasty, or carotid endarterectomy) less than 3 months prior to screening, unstable cardio- or cerebrovascular disease, clinically significant valvular disease requiring treatment with anticoagulant, congestive heart failure (CHF) or other Class III or IV cardiovascular symptoms according to New York Heart Association (NYHA) functional classification, uncontrolled diabetes mellitus defined as HbA1c value > 10 %, blood coagulation disorder, any psychiatric illness, drug addiction within a year prior to enrollment in the study, severe hepatic dysfunction, patients with positive serology for HIV, HBV and HCV, history of malignancy, treated or untreated, within the past 5 years, with the exception of successfully treated basal cell or squamous cell carcinoma of the skin, previous participation in any clinical trial within 1 month before the entry of the study, history of seizure and alcoholism, pregnant and lactating woman and use of corticosteroids (except the use of inhaled steroids for asthma), bisphosphonates, acid suppressants, prostaglandin analogues or anticoagulant or NSAID within last 4 weeks prior to screening or their planned co-prescription during the study participation.

4. Study procedures and drugs

After signing the informed consent form, the subjects were screened to assess eligibility according to the study selection criteria. Upon fulfillment of the selection criteria, subjects were randomized using Interactive Web Response System (IWRS) in 2:1 ratio (i.e. 160 subject in Aspirin 150 mg + Pantoprazole 20 mg test group and 80 subjects in Aspirin 150 mg comparator group) to enter into the treatment period of 6 months (24 weeks). Randomization was stratified based on their baseline Lanza score i.e. Lanza score of 0–1 and Lanza score of 2. The randomization schedule was generated using SAS® (SAS Institute Inc., USA). As this was double blind study, the subjects, the study team (investigators or their designee, sponsor or their designee, contract research organization (CRO) or their designee, Gastroenterologists/designee), or any other relevant personnel involved in conduct and interpretation of the study results were blinded to the administration of investigational product. To maintain this blindness, double dummy design was used during the study. Patients in test group were asked to take one capsule of FDC of Aspirin 150 mg + Pantoprazole 20 mg and one placebo tablet (similar to comparator) while patients in the comparator group were asked take one tablet of Aspirin 150 mg and one placebo capsule (similar to the test product).

Patients were screened during visit 1 on the basis of demographics, patient characteristics, physical examination, vital signs, past medical history, medication history, ECG, 2D ECHO, gastro duodenal endoscopy, heartburn assessment, laboratory investigations and urine analysis (Fig. 1) The study consisted of screening period (1 week), 6 months (24 weeks) of treatment period, and follow up period, 1 week after completion of treatment period. Patients were instructed to take the assigned investigational products orally, once daily in the morning with water, approximately 1 h prior to the first meal of the day for 6 months. Patients were instructed to swallow intact, not to chew, crush or open the capsule and not to chew or crush the tablet. Patients were followed up on week 2, 6, 12, 18 and 24. Designated study personnel assessed treatment compliance at each visit by accountability check and by review of the patient diary. During each clinic visit, adverse events and concomitant medication used (including NSAID use) were assessed.

Fig. 1.

Flow of patients in the study.

5. Efficacy and safety assessments

Primary efficacy endpoint was to compare proportion of patients developing gastro duodenal events (Non-responder) in both the treatment groups at 12 & 24 weeks. Secondary efficacy endpoints were mean change in Lanza score from baseline to 12 & 24 weeks in both groups, proportion of patients worsening in terms of Lanza score from baseline in both groups, mean change in heartburn score in both groups and usage of antacid in both groups. Safety endpoints were Treatment Emergent serious and non-serious Adverse Events (TEAEs) and worsening of clinical laboratory parameters.

6. Statistical analyses

Sample size calculations indicated that 240 participants would be needed in both groups with sampling ratio of 2:1 to achieve 80 % power with an alpha level of 0.05 (two tailed), if the minimal expected difference in proportions is 20 % and considering 20 % drop-out. Patient having gastroduodenal events (defined as developing new erosions as compared tobaseline) was considered as non-responder and with same or decrease in number of erosions were considered as responder. Chi–Square test was used for the comparison of categorical variables and unpaired t-test was used to compare continuous variables. In addition to p-value of the test, for the difference in responders between the two treatment groups was calculated. P-value <0.05 was considered statistically significant. Modified intention-to-treat (mITT) analysis with Last observation Carry Forward (LOCF) was used for this study.

7. Results

Table 1 highlights the demographic characteristics of the patients inluded in the present study. The primary efficacy endpoint i.e. proportion of non-responders (patients having gastroduodenal events – developing new erosions as compared to baseline) were 9.7 % in test group (Fixed dose combination of aspirin 150 mg and pantoprazole 20 mg) as compared to 19.7 % in the comparator group (aspirin 150 mg) at week 12, while at 24 weeks, the proportion of non-responders were 11.0 % in the test group as compared to 22.4 % in the comparator group. P – value was <0.05 at week 12 and 24 as shown in Table 2.

Table 1.

Demographic and other baseline characteristics.

	Test (N = 160)	Comparator (N = 80)	p-value
Age (years)	63.8 ± 6.87	63.7 ± 6.45	0.9354
Height (cm)	160.47 ± 8.829	161.89 ± 8.358	0.2445
Weight (Kg)	63.97 ± 9.160	64.29 ± 9.162	0.4725
Race
Asiana	160 (100)	80 (100)
Gender
Malea	110 (68.8)	50 (62.5)
Femalea	50 (31.3)	30 (37.5)
Ethnicity
Non – hispanic or Latinoa	160 (100)	80 (100)

Test: Fixed dose combination of Aspirin 150 mg and Pantoprazole 20 mg.

Comparator: Aspirin 150 mg.

Data expressed as mean ± SD. p-values based on unpaired t-test.

^aData expressed as n (%).

Table 2.

Primary Efficacy End Point: Proportion of patients developing new gastro duodenal events (Non-responders).

Visit	Parameter	Test (N = 154)	Comparator (N = 76)	Difference in % of Non-responders & P Value
Visit 5 (Week 12)	Proportion of Non-Responders	15 (9.7)	15 (19.7)	10.0 (0.21; 21.32) & 0.0285
	Proportion of Responders	134 (87.0)	57 (75.0)
Visit 7 (Week 24)	Proportion of Non Responders	17 (11.0)	17 (22.4)	11.33 (0.73; 21.93) & 0.0228
	Proportion of Responders	137 (89.0)	59 (77.6)

Test: Fixed dose combination of Aspirin 150 mg and Pantoprazole 20 mg.

Comparator: Aspirin 150 mg.

Data presented as n (%).

P Value based on Chi-square Test.

In the secondary endpoint analysis, the mean (±SD) change in Lanza score from baseline to week 12 was −0.054 ± 0.7424 in the test group compared to 0.153 ± 0.7811 in the comparator group, which approached statistical significance (p-value 0.0581). The mean (±SD) change in Lanza score from baseline to week 24 was −0.208 ± 0.7977 in the test group compared to −0.092 ± 0.9685 in the comparator group, but this difference was not statistically significant (p-value 0.3691). However, a statistically significant improvement in the Lanza score from baseline to week 24 was observed in the test group (p-value 0.0015) compared to the comparator group (p-value 0.4097) (Table 3).

Table 3.

Secondary Efficacy End Points: Mean change in Lanza score, Heartburn score and number of erosions.

Visit	Test (N = 154)	Comparator (N = 76)	P – valueb
Lanza Score
Visit 1 (Baseline)	0.610 ± 0.8805	0.618 ± 0.8789	0.9481
Visit 5 (Week 12)	0.577 ± 0.8713	0.750 ± 0.9457	0.1804
Change from baseline to week 12	−0.054 ± 0.7424	0.153 ± 0.7811	0.0581
Visit 7 (Week 24)	0.403 ± 0.7455	0.526 ± 0.8714	0.2646
Change from baseline to week 24	−0.208 ± 0.7977a	−0.092 ± 0.9685	0.3691
Heartburn score
Visit 1 (Baseline)	0.325 ± 0.5098	0.447 ± 0.5265	0.0908
Visit 5 (Week 12)	0.235 ± 0.4554	0.303 ± 0.4624	0.2957
Change from baseline to week 12	−0.059 ± 0.5409	−0.053 ± 0.5137	0.9340
Visit 7 (Week 24)	0.176 ± 0.3825	0.250 ± 0.4655	0.2646
Change from baseline to week 24	−0.111 ± 0.5201a	−0.105 ± 0.6018	0.1315
Number of erosions
Visit 1 (Baseline)	1.396 ± 2.4877	1.145 ± 2.0113	0.4119
Visit 5 (Week 12)	1.228 ± 2.9158	1.528 ± 2.6695	0.4629
Change from baseline to week 12	−0.215 ± 2.6523	0.528 ± 2.4551	0.0470
Visit 7 (Week 24)	0.968 ± 2.5754	1.474 ± 3.6276	0.2787
Change from baseline to week 24	−0.429 ± 2.0859a	0.329 ± 3.2224	0.0648

Test: Fixed dose combination of Aspirin 150 mg and Pantoprazole 20 mg.

Comparator: Aspirin 150 mg.

Data expressed as mean ± SD.

^aP < 0.05 (based on Paired T test; as compared to baseline).

^bP values based on Un-paired T test.

The mean (±SD) change in Heartburn score from baseline to week 12 and week 24 between the test and comparator groups was not statistically significant (p-value 0.9340). However, a statistically significant improvement in the Heartburn score from baseline to week 24 was observed in the test group (p-value 0.0091) compared to the comparator group (p-value 0.1315). It was noted that none of the subjects required any antacid treatment (Table 3).

The mean (±SD) change in the number of erosions from baseline to week 12 was statistically significant (p-value 0.0470) between the test and comparator groups, while at week 24, it approached statistical significance (p-value 0.0648). However, a statistically significant improvement in the number of erosions from baseline to week 24 was observed in the test group (p-value 0.0118) compared to the comparator group (p-value 0.3763) (Table 3). Further, the proportion of patients worsening in terms Lanza score is shown in Table 4.

Table 4.

Patients worsening in terms of Lanza score from baseline.

Visit	Parameter	Test (N = 154)	Comparator (N = 76)	Difference in % of Non-responders & P Value
Visit 5 (Week 12)	Proportion of Non-Responders	14 (9.1)	13 (17.1)	8.66 (−1.38; 18.7) & 0.0698
	Proportion of Responders	135 (87.7)	59 (77.6)
Visit 7 (Week 24)	Proportion of Non Responders	15 (9.7)	12 (15.8)	6.05 (−3.39; 15.49) & 0.1839
	Proportion of Responders	139 (90.3)	64 (84.2)

Test: Fixed dose combination of Aspirin 150 mg and Pantoprazole 20 mg.

Comparator: Aspirin 150 mg.

Data presented as n (%).

P Value based on Chi-square Test.

Out of 36 treatment-emergent adverse events (TEAEs), 23 adverse events were reported in 18 (11.3 %) patients in the test group (i.e., Fixed dose combination of Aspirin 150 mg and Pantoprazole 20 mg), and 13 adverse events were reported in 11 (13.8 %) patients in the comparator group (i.e., Aspirin 150 mg). The common TEAEs reported in the test group, with an incidence of ≥1 %, were neutropenia (1.3 %), epistaxis (1.3 %), anemia (1.9 %), and headache (1.9 %). In the reference group, the common TEAEs reported, with an incidence of ≥1 %, were neutropenia (1.3 %), nausea (1.3 %), cellulitis (1.3 %), periarthritis (1.3 %), headache (1.3 %), hematuria (1.3 %), urinary tract infection (1.3 %), decreased hemoglobin (2.5 %) and bacterial urinary tract infection (3.8 %) (Table 5).

Table 5.

Summary of treatment emergent adverse events.

All TEAEs	Test (N = 160)	Comparator (N = 80)
	18(11.3)	11(13.8)
TEAEs Related to IMP
Treatment not related	7(4.4)	6(7.5)
Treatment related	14(8.8)	5(6.3)
Severity of TEAEs
Grade 1 (Mild)	11(6.9)	10(12.5)
Grade 2 (Moderate)	8(5.0)	2(2.5)
Grade 3 (Severe)	0(0.0)	0(0.0)
Serious TEAEs	0(0.0)	0(0.0)

Data presented as n(%).

TEAE: Treatment emergent adverse events.

N: Number of subjects dosed with each treatment; n: Number of subjects with adverse event with particular category; %: Calculated using the number of subjects treated with each treatment as the denominator (n/N)*100.

Test: Fixed dose combination of Aspirin 150 mg and Pantoprazole 20 mg.

Comparator: Aspirin 150 mg.

There was no statistically significant difference observed in change from baseline to week 24 for hematology and biochemistry laboratory parameters between two treatment groups.

8. Discussion

This study presents the results of the randomized, double blind study comparing the efficacy and safety of fixed dose combination of aspirin and pantoprazole versus aspirin alone for the prevention of gastro mucosal damage in Indian patients receiving aspirin therapy. The study showed statistically significant change in almost all efficacy variables like development of gastro-duodenal events, mean change in Lanza score and change in number of erosions from baseline to week 24 in the test group. It was noted during the study that the number of erosions decreased at week 12 and 24 (statistical significant) as compared to baseline in test group. However, the number of erosions increased at week 12 and 24 as compared to baseline in comparator group. It was further noted that the mucosal damage tapered off from week 12–24 in the comparator group however its clinical significant is unknown and it could be chance effect.

The results of our study are consistent with those of other internationally published studies. The randomized ASTERIX trial demonstrated that esomeprazole 20 mg reduces the incidence of peptic ulcers in patients using low-dose aspirin continuously. During the 26-week treatment period, 5.4 % of patients in the placebo group developed a gastric or duodenal ulcer compared to 1.6 % of patients in the esomeprazole group (p-value = 0.0007). Additionally, at the 26-week mark, the cumulative proportion of patients with erosive esophagitis was significantly lower in the esomeprazole group compared to the placebo group.¹⁴ Our study's results also revealed a significantly higher proportion of patients experiencing a reduction in gastro duodenal events at 12 and 24 weeks in the pantoprazole + aspirin group compared to the aspirin-alone group.

The OBERON trial examined the effects of PPI therapy versus placebo in individuals initiating aspirin therapy. The trial data aligns with and expands upon the findings of the ASTERIX trial. Both doses of esomeprazole (40 mg and 20 mg) significantly decreased the cumulative proportion of patients developing peptic ulcers. Only 1.5 % of esomeprazole 40 mg recipients and 1.1 % of esomeprazole 20 mg recipients developed peptic ulcers compared to 7.4 % of placebo recipients (both p-value <0.0001 versus placebo) which is consistent with our study. It is important to note that the OBERON trial enrolled participants who were aspirin-naïve and had a previous history of uncomplicated peptic ulcer disease,¹⁰ while our trial enrolled patients with stable cardiovascular disease who had been on long-term aspirin therapy before study enrollment. We specifically excluded patients who were already receiving PPI therapy and those at high risk of peptic ulcer disease.

The prevention of ulcer occurrence would reduce the incidence of ulcer bleeds and other complication, based on this fact, ulcers confirmed by endoscopy have been used as clinical markers of gastrointestinal end points.¹⁵ There is definite evidence that PPIs decrease hospitalizations due to serious gastrointestinal bleeding among patients taking aspirin or non-steroidal anti-inflammatory drugs.¹⁶ Peptic ulcers with gastrointestinal bleeding may affect the underlying cardiovascular disease because peptic ulcers can cause anaemia,¹⁷ can cause hospitalization in patients with myocardial infarction and also can be a high risk factor for mortality.¹⁸ Gastrointestinal bleeding is also an independently associated with ischemic complications in patients with cardiovascular disease and can cause mortality.¹⁹

The Clopidogrel and Optimisation of Gastrointestinal Events Trial (COGENT) demonstrated that the rate of upper gastrointestinal bleeding was significantly reduced by prophylactic PPI therapy among patients taking dual antiplatelet treatment without a significant increasing cardiovascular events.¹¹ The data from the trial showed that gastrointestinal event rate was 1.1 % with omeprazole and 2.9 % with placebo at 180 days (p-value <0.001). The rate of upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (p-value = 0.001).¹¹

The benefit of PPI treatment has been previously demonstrated in patients who are at very high gastrointestinal risk and receiving low-dose aspirin, using ulcer complications as end points.²⁰ Concomitant low-dose aspirin and esomeprazole treatment significantly reduced the risk of recurrent ulcer bleeding compared with clopidogrel monotherapy in patients at increased cardiovascular risk.²¹ Based on these data, American College of Gastroenterology, American Heart Association and American College of Cardiology Foundation has given the joint statement that PPIs can be used for gastro-protection among patients with gastrointestinal risk factors who are receiving low-dose aspirin or clopidogrel for treatment of cardiovascular disease.²²

FDCs have become increasingly common in clinical practice now a days.^23,24 FDCs are frequently prescribed for the treatment of various disorders, including cardiovascular and cerebrovascular diseases, diabetes, HIV infection, tuberculosis, bacterial infections, respiratory diseases, gastrointestinal infections, cough and cold.²⁵ In this study, we utilized a fixed dose combination of pantoprazole + aspirin which helps reduce pill burden, especially in elderly patients who often have a high pill count. FDCs can significantly improve patient compliance, thereby preventing serious complications and ensuring better treatment outcomes. Additionally, they enhance the effectiveness of the drugs and reduce the occurrence of adverse drug reactions. FDCs are convenient to use, simplify medication management and are more cost-effective compared to individual drugs.¹³

One of the limitations of the present study was its sample size, which was sufficient to demonstrate differences in primary efficacy parameter but not enough to detect significant differences in the secondary efficacy and safety parameters of the two drugs. However, differences in safety parameters are more likely to be observed in long-term, large-scale post-marketing studies, as they can be challenging to detect in randomized controlled studies. Another limitation of the study was platelet function assays were not performed among two groups.

9. Conclusion

Fixed dose combination of aspirin 150 mg and pantoprazole 20 mg was found more efficacious and safer as compared to aspirin 150 mg alone for the prevention of gastro duodenal mucosal damage in patients receiving aspirin.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.