Proton-pump inhibitors: use and effectiveness in ACS patients receiving dual antiplatelet therapy

We performed a cross-sectional study to determine the frequency of use of proton-pump inhibitors (PPIs) in acute coronary syndrome (ACS) patients on dual antiplatelet therapy (DAPT) within 24 hours of hospital admission, and their effectiveness in reducing bleeding complications.

This cross-sectional study included a total of 83 patients admitted via the medical take to Queen Elizabeth Hospital, Lewisham and Greenwich Trust (LGT), London, with ACS from May 2022 to June 2022. The data of these patients were analysed to see whether ACS patients on DAPT were given PPIs within 24 hours of their hospital admission. These patients were further assessed for any bleeding event during their hospital admission and its association with the prescription of PPIs.

A significant number of ACS patients (26, 32.1%) were not prescribed PPIs within 24 hours of hospital admission. However, 55 (67.9%) patients were prescribed PPIs within 24 hours of their hospital admission. Of the 26 ACS patients not given PPIs within 24 hours of their hospital admission, three patients developed bleeding complications during their admission. Two out of the three patients developed gastrointestinal (GI) bleeding (melena) with a significant drop in their haemoglobin levels, while one patient developed haematuria.

In conclusion, a large number of patients admitted with ACS and started on DAPT did not receive a concomitant PPI within 24 hours of admission to the hospital in accordance with European Society of Cardiology (ESC) and American Heart Association (AHA) guidelines, and, as such, were at significant risk of bleeding events.

Introduction

Dual antiplatelet therapy (DAPT) comprises a combination of aspirin and thienopyridine agents, such as clopidogrel, prasugrel and ticagrelor. DAPT is the cornerstone of treatment of patients presenting with acute coronary syndrome (ACS), undergoing either medical therapy alone or percutaneous coronary intervention (PCI).^1,2 There has been considerable progress in the treatment of ACS with the advent of more potent agents, in addition to therapeutic anticoagulation. DAPT has contributed to improved outcomes in patients presenting with ACS, with numerous studies showing a marked reduction in major adverse cardiovascular and cerebrovascular events (MACCE).³ Moreover, DAPT has led to a decreased risk of cerebrovascular accidents (CVA) and myocardial infarction (MI).⁴

A considerable limitation of DAPT is the increased risk of bleeding events, resulting sometimes in early termination of dual therapy, which in itself can contribute to higher MACCE.⁵ It is also well established that bleeding alone can increase the risk of MACCE, and the most common source of bleeding secondary to DAPT therapy is the gastrointestinal (GI) tract.⁶

An expert consensus statement has recommended the use of proton-pump inhibitors (PPIs) in ACS patients, on admission, in addition to DAPT, as an effective approach to decrease the incidence of GI bleeding.⁷ As a result, the combination of DAPT and PPI in ACS patients on admission represents a plausible way to decrease the risk of adverse cardiovascular events, as well as GI bleeding.

It is recognised that not all patients with ACS are appropriately initiated on concomitant DAPT and PPI therapy upon admission, hence exposing them to increased risk of significant GI bleeding, which can consequently lead to de-escalation to single antiplatelet therapy (SAPT). This may then have an impact on the decision to offer guideline-directed revascularisation (GDR) for ACS during index hospitalisation, and may then potentially contribute to increased risk of MACCE where GDR is not performed. In our study, we assessed the frequency of use of PPIs in ACS patients receiving DAPT on hospital admission and determined the association between failure to use PPIs and its deleterious consequences (GI bleeding) in these patients during hospitalisation.

Materials and method

This cross-sectional study involved a total of 83 patients, taken by non-probability consecutive sampling, admitted to Queen Elizabeth Hospital, Lewisham and Greenwich Trust (LGT), London, presenting with ACS from May 2022 to June 2022. We analysed the data to see if patients who were prescribed DAPT for the ACS were also prescribed any PPI within 24 hours of hospital admission. For those not prescribed a PPI, we assessed if they suffered any significant bleeding events. Patients who had a contraindication to use of DAPT (previous history of aspirin allergy or ongoing significant bleeding with low haemoglobin necessitating use of SAPT) were excluded.

The Chi-square test was used to determine the association between non-prescription of PPI within 24 hours of admission of ACS patients on DAPT and upper GI bleeding. Statistical significance was indicated by p values less than 0.05. Statistical calculations were performed using SPSS version 20 software.

Results

Data from 81 patients were collected; 27 patients (33.3%) were female and 54 patients (66.7%) were male. The mean age of the patients was 66 years (range 32–93 years). Among patients included in the study, eight patients (9.9%) were frail while 73 patients (90.1%) were non-frail. Frailty was assessed by clinical frailty score (CFS).⁸

A large number of ACS patients (26, 32.1%) were not prescribed PPIs within 24 hours of their hospital admission. Conversely, 55 (67.9%) of the patients were prescribed PPIs (lansoprazole, pantoprazole and omeprazole) within 24 hours of their hospital admission. Out of these 55 patients, 41 (74.5%) patients were given lansoprazole, 13 (23.6%) patients were given omeprazole and one (1.8%) patient was given pantoprazole.

Of 26 ACS patients who were not given PPIs within 24 hours of their hospital admission, three patients developed bleeding complications during the course of their hospital admission. Two of the three patients developed GI bleeding (melena) with a significant drop in their haemoglobin (Hb) levels (p=0.037) while one patient developed haematuria. Blood transfusion was not required in any of these patients. A summary of the results is presented in table 1.

Discussion

Thienopyridines are used in combination with aspirin (DAPT) or in place of aspirin to reduce cardiovascular events. Clopidogrel and prasugrel require activation of cytochrome P450 enzymes, inhibiting platelet aggregation by blocking the binding of adenosine diphosphate (ADP) to its P2Y12 receptors.⁹

Combination therapy of aspirin and clopidogrel (DAPT) compared with aspirin only, is associated with a reduction in the event rate of MI and CVA, as well as cardiac mortality from 11.4% to 9.3% (p<0.001) in non-ST-elevation ACS (NSTE-ACS) patients; this is regardless of whether the patients were managed with medical therapy alone or adjunct revascularisation. However, DAPT is associated with an increased rate of significant bleeding from 2.7% to 3.7% (p=0.001).¹ As prasugrel has greater potency with fewer steps for activation via the liver, as compared with clopidogrel, it is more effective than clopidogrel in its antithrombotic role.³ Not surprisingly, there is also an increased risk of bleeding as seen in the Greek Antiplatelet (GRAPE) study where bleeding events (Bleeding Academic Research Consortium; BARC of any type) occurred more frequently in ACS patients treated with prasugrel (51.2%) compared with those who were treated with clopidogrel (37.6%) (hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.33 to 1.95, p<0.001).¹⁰

Ticagrelor is also a more potent antiplatelet agent than clopidogrel,¹¹ not requiring any activation.³ In the GRAPE study, there were greater bleeding events (BARC, any type) in patients treated with ticagrelor (56.9%) as compared with those patients treated with clopidogrel (HR 1.81, 95%CI 1.55 to 2.10, p<0.001).¹⁰

GI erosions or ulcers are not directly caused by thienopyridines,¹² rather their platelet-inhibiting activity increases the risk of bleeding at places where lesions have already formed secondary to nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin or Helicobacter pylori infection.¹³ Reduction in gastric acid synthesis leads to improved healing of GI erosions and ulcers, and, thereby, may result in lower risk of GI bleeding with thienopyridine therapy.¹⁴

Gastric acid synthesis can be reduced by both histamine H₂ receptor antagonists and PPIs, but PPIs can suppress the acid production more effectively and for up to 36 hours.¹⁵ Many observational studies have shown that patients taking antiplatelet treatment had a significant reduction in GI bleeding with concomitant use of PPIs. One such study showed a 50% reduction in clopidogrel-related GI bleeding with an absolute risk reduction of 2.8% per annum in high-risk patients.¹⁶ Lanas et al. studied 2,779 patients having upper GI bleed evidenced on endoscopy with 5,532 controls, and showed that when a combination of antiplatelet therapy and PPIs were used, there was a significant reduction in upper GI haemorrhage in comparison with the use of antiplatelet therapy alone.¹⁷ Other studies have also demonstrated a similar significant reduction in GI bleeding with the use of PPIs in conjunction with thienopyridine therapy.¹⁸

In COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial),¹⁹ there was a significant reduction in upper GI bleeding in patients taking a combination of DAPT and the PPI omeprazole (1.1%) compared with those taking only DAPT (2.9%) (HR 0.34, 95%CI 0.18 to 0.63). Moreover, no significant differences were found between the two study groups in terms of non-fatal MI, CVA, revascularisation and cardiovascular mortality. In our study, no ACS patient developed GI bleeding while taking a combination of DAPT and PPI. On the other hand, 11.5% ACS patients developed bleeding complications while on DAPT therapy without a PPI. Among them, two out of three patients developed GI bleeding while one patient developed urinary tract bleeding.

The American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association (ACCF/ACG/AHA) 2010 expert consensus document⁷ recommends the use of PPIs in combination with DAPT in patients with a history of GI bleeding, concurrent anticoagulant therapy (as in ACS patients) and in patients with at least two high-risk factors for bleeding, which include patients with history of dyspepsia, gastro-oesophageal reflux disease, H. pylori infection, chronic alcohol use, chronic NSAID/corticosteroid use and patients ≥65 years of age (class IIa). These limited PPI indications by the ACCF/ACG/AHA 2010 expert consensus are meant to avoid complications of long-term PPI use, as many studies showed that long-term PPI use alters intestinal microbiota and is an independent risk factor associated with NSAID-associated enteropathy.^20,21 On the other hand, 2018 European Society of Cardiology (ESC) guidelines recommend regular PPI usage in all patients taking DAPT (class I, level of evidence B).²²

Use of PPIs has been progressively increasing over time in ACS patients taking DAPT, irrespective of the risk of GI bleeding. Danish national-level research showed that only 40% of patients, including patients at high risk of bleeding, used PPIs within seven days of hospital discharge in the year 2014.²³ A Dutch study showed an increase in PPI therapy at the time of hospital discharge from 34.7% in 2010 to 88.7% in 2014.²⁴ US-based research showed that 41% of ACS patients took PPIs with clopidogrel in the year 2016.²⁵

Despite the ACCF/ACG/AHA and recent ESC recommendations, our study showed a large proportion of ACS patients (32.1%) were not prescribed PPIs within 24 hours of hospital admission, leading to bleeding complications and adverse outcomes.

Conclusion

A large number of patients admitted with ACS on DAPT did not receive a concomitant PPI within 24 hours of admission to the hospital in accordance with ESC and AHA guidelines, resulting in significant GI bleeding events.

Key messages

• Dual antiplatelet therapy (DAPT) combined with therapeutic anticoagulation is the cornerstone of antithrombotic treatment for patients with acute coronary syndrome (ACS). While this approach has markedly improved clinical outcomes, it also increases the risk of bleeding, particularly from the gastrointestinal (GI) tract
• American Heart Association (AHA) and European Society of Cardiology (ESC) guidelines recommend the concurrent use of proton-pump inhibitors (PPIs) for these patients to mitigate the risk of bleeding
• This study found that a large number of ACS patients on DAPT did not receive a concomitant PPI, leading to a significant incidence of GI bleeding
• Adhering to ESC and AHA guidelines by prescribing PPIs alongside DAPT for ACS patients can substantially reduce the occurrence of bleeding complications

Conflicts of interest

None declared.

Funding

None.

Study approval

Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research. Ethical approval for the study was granted by the local ethics committee (reference number: 7255).

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