Use anti-proton pump inhibitors to effectively prevent gastrointestinal bleeding caused by antiplatelet therapy

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The harm of arterial thrombosis to human health is now well known, and antiplatelet therapy has become an indispensable link in the prevention and treatment of arterial thrombotic diseases and reducing the risk of ischemic events after percutaneous coronary intervention ( thrombotic PCI ) .

However, while antiplatelet therapy protects the cardiovascular and cerebrovascular , the blood vessels " fire in the backyard " - there is a risk of drug-induced upper gastrointestinal injury and bleeding .
How to prevent drug-induced gastrointestinal injury caused by antiplatelet therapy has been called ups and downs .
Digestion Prevention Digestion

Antiplatelet drugs " protect the heart " but " damage the stomach "

Antiplatelet drugs " protect the heart " but " damage the stomach " Antiplatelet drugs " protect the heart " but " damage the stomach "

In the past three decades, antiplatelet drugs have been widely used in the prevention and treatment of cardiovascular and cerebrovascular diseases
.

But people have long discovered that antiplatelet drugs are a " double-edged sword " .
On the one hand, they can " protect the heart " - inhibit platelet activation and thrombosis, and protect people's cardiovascular and cerebrovascular health; on the other hand, they can "protect the heart" " Stomach damage " - damage to the gastrointestinal mucosa, leading to ulceration and bleeding, that is, drug-induced gastrointestinal injury (Figure 1 )

In the past three decades, antiplatelet drugs have been widely used in the prevention and treatment of cardiovascular and cerebrovascular diseases

Figure 1Mechanism of drug-induced gastrointestinal injury of aspirin and clopidogrel [1] 

Figure 1Mechanism of drug-induced gastrointestinal injury of aspirin and clopidogrel [1] 

Even low-dose aspirin may increase the risk of gastrointestinal injury, clopidogrel can aggravate gastrointestinal injury, and the risk is higher when aspirin and clopidogrel are used in combination [2]
.

A case-control study [3] showed that the OR values ​​of different antiplatelet drugs for upper gastrointestinal bleeding were: low-dose aspirin 1.
8 , clopidogrel 1.
1 , dipyridamole 1.
9 , and vitamin K antagonist ( VKA ) 1.
8 ; While aspirin combined with VKA was 5.

Even low-dose aspirin may increase the risk of gastrointestinal injury, clopidogrel can aggravate gastrointestinal injury, and the risk is higher when aspirin and clopidogrel are used in combination [2]

Combination PPIs prevent antiplatelet therapy Combination PPIs prevent antiplatelet therapy

drug-induced gastrointestinal injury

drug-induced gastrointestinal injury

According to the consensus of experts in China [2] , in order to reduce the gastrointestinal damage caused by antiplatelet drugs , necessary gastrointestinal protection should be given while standardizing and rationally using antithrombotic drugs, evaluating and screening patients with high bleeding risk (Figure 2 ).

, such as screening and eradication of H.
pylori , high-risk patients are given effective acid-suppressing drugs at the same time, the first choice is proton pump inhibitor ( PPI )

According to the consensus of experts in China [ 2] , in order to reduce the gastrointestinal damage caused by antiplatelet drugs , necessary gastrointestinal protection should be given while standardizing and rational use of antithrombotic drugs, evaluating and screening patients with high bleeding risk (Fig .
Check 2 ), such as screening and eradicating H.

Figure 2   Antiplatelet therapy for the prevention of drug-induced gastrointestinal injury 

Figure 2   Antiplatelet therapy for the prevention of drug-induced gastrointestinal injury 

The efficacy of PPI is better than that of H2RA , and it was recommended by domestic and foreign guidelines as early as ten years ago [4-7] as the drug of choice for the prevention of antiplatelet drug-related gastrointestinal injury
.

In recent years, it is still the recommended concomitant drug for cardiovascular disease antithrombotic therapy, especially combined antithrombotic therapy ( DAPT ), to reduce gastrointestinal bleeding

The efficacy of PPI is better than that of H2RA , and it was recommended by domestic and foreign guidelines as early as ten years ago [4-7] as the drug of choice for the prevention of antiplatelet drug-related gastrointestinal injury .
In recent years, it is still the recommended concomitant drug for cardiovascular disease antithrombotic therapy, especially combined antithrombotic therapy ( DAPT ), to reduce gastrointestinal bleeding .

A large randomized, double-blind, placebo-controlled study ( COGENT ) [8] enrolled 3761 patients with acute coronary syndrome ( ACS ), a history of coronary stenting at low risk of gastrointestinal bleeding , randomized to antiplatelet Combined PPI test group ( n=1876 ) and antiplatelet combined with placebo control group ( n=1885 ) .

The results showed that prophylactic use of PPIs in patients receiving DAPT significantly reduced the risk of upper gastrointestinal bleeding ( 1.
1% vs.
2.
9% , P<0.

A large randomized, double-blind, placebo-controlled study ( COGENT ) [8] enrolled 3761 patients with acute coronary syndrome ( ACS ) with a low risk of gastrointestinal bleeding, a history of coronary stenting, randomized Divided into antiplatelet combined with PPI experimental group ( n=1876 ) and antiplatelet combined with placebo control group ( n=1885 )

For PPI , antiplatelet therapy is for PPI , antiplatelet therapy

Really worry-free

Really worry-free, really worry-free

However, just when people thought that the gastrointestinal bleeding problem with antiplatelet therapy had been resolved and they could breathe a sigh of relief, the unexpected happened
.

A retrospective cohort study [9] published in the journal JAMA in 2009 found that patients with acute coronary syndrome ( ACS ) taking PPIs concurrently with clopidogrel antiplatelet were at increased risk of readmission for ACS , and their overall health was increased.
The mortality rate is higher than that of patients who only use clopidogrel - does clopidogrel seem to " fail " ?

However, just when people thought that the gastrointestinal bleeding problem with antiplatelet therapy had been resolved and they could breathe a sigh of relief, the unexpected happened
.
A retrospective cohort study [9] published in the journal JAMA JAMA in 2009 found that patients with acute coronary syndrome ( ACS ) taking PPIs concurrently with clopidogrel antiplatelet had an increased risk of readmission due to ACS , and the patient's All-cause mortality was higher than that of patients who only used clopidogrel - as if clopidogrel " failed " ?

Pharmacological mechanism studies have revealed the reason behind: Clopidogrel needs to be converted into active metabolites in the liver before it can bind to the P2Y12 receptor on the platelet membrane, thereby exerting antiplatelet activity
.
The key enzyme in its metabolism is the cytochrome P450 isoenzyme CYP2C19 (and CYP3A4 also plays a role) - and CYP2C19 is also the metabolic enzyme of most PPIs in the liver
.

Pharmacological mechanism studies have revealed the reason behind: Clopidogrel needs to be converted into active metabolites in the liver before it can bind to the P2Y12 receptor on the platelet membrane, thereby exerting antiplatelet activity
.
The key enzyme in its metabolism is the cytochrome P450 isoenzyme CYP2C19 (and CYP3A4 also plays a role) - and CYP2C19 is also the metabolic enzyme of most PPIs in the liver
.

Studies have confirmed that both CYP2C19 gene polymorphisms and CYP2C19 inhibitors can affect the antiplatelet effect of clopidogrel [2]
.
And theoretically, any drug or substance metabolized by CYP2C19 may affect the metabolism of clopidogrel through the competitive inhibition effect, thereby affecting the antiplatelet effect of clopidogrel
.
Therefore, it may be the drug interaction between PPI and clopidogrel that prevents clopidogrel from exerting its therapeutic effect
.

Studies have confirmed that both CYP2C19 gene polymorphisms and CYP2C19 inhibitors can affect the antiplatelet effect of clopidogrel [2]
.
And theoretically, any drug or substance metabolized by CYP2C19 may affect the metabolism of clopidogrel through the competitive inhibition effect, thereby affecting the antiplatelet effect of clopidogrel
.
Therefore, it may be the drug interaction between PPI and clopidogrel that prevents clopidogrel from exerting its therapeutic effect
.

Fortunately, the interaction between PPI and clopidogrel is not a class effect [11] .
Different PPIs have different competitive inhibitory effects on CYP2C19 [12] , omeprazole and esomeprazole have the strongest effect, and rabeprazole has the weakest effect (Figure 3 ) .

Fortunately, the interaction between PPI and clopidogrel is not a class effect [11] .
Different PPIs have different competitive inhibitory effects on CYP2C19 [12] , omeprazole and esomeprazole have the strongest effect, and rabeprazole has the weakest effect (Figure 3 ) .

Figure 3   Competitive inhibition of CYP2C19 by different PPIs

Figure 3   Competitive inhibition of CYP2C19 by different PPIs

Omeprazole is mainly metabolized by CYP2C19 , and it is also a strong inhibitor of CYP2C19 , so it will have obvious drug interactions with clopidogrel .
Rabeprazole is mainly (about 85% ) metabolized by non-enzymatic pathway to form the thioether rabeprazole [13] , and only a small amount of CYP2C19 and CYP3A4 are involved in metabolism.
Therefore, the effect of rabeprazole is more affected by CYP2C19 genotype.
small .

Omeprazole is mainly metabolized by CYP2C19 , and it is also a strong inhibitor of CYP2C19 , so it will have obvious drug interactions with clopidogrel .
Rabeprazole is mainly (about 85% ) metabolized by non-enzymatic pathway to form the thioether rabeprazole [13] , and only a small amount of CYP2C19 and CYP3A4 are involved in metabolism.
Therefore, the effect of rabeprazole is more affected by CYP2C19 genotype.
small .

The Chinese population carries a higher frequency of CYP2C19 loss-of-function alleles ( 38% ), which has a more significant impact on the antiplatelet effect of clopidogrel [14] , and more attention should be paid when choosing PPIs .
Most studies in East Asian populations have shown that PPI effects on clopidogrel efficacy can be minimized by using a novel PPI (rabeprazole) with a weaker affinity for CYP2C19 genotypes [15] .

The Chinese population carries a higher frequency of CYP2C19 loss-of-function alleles ( 38% ), which has a more significant impact on the antiplatelet effect of clopidogrel [14] , and more attention should be paid when choosing PPIs .
Most studies in East Asian populations have shown that PPI effects on clopidogrel efficacy can be minimized by using a novel PPI (rabeprazole) with a weaker affinity for CYP2C19 genotypes [15] .

A recent prospective, randomized, parallel-group pharmacodynamic study ( PROTECT study) also showed that rabeprazole compared with famotidine even in clopidogrel-sensitive patients with a high incidence of drug interactions.
Does not reduce the efficacy of DAPT [16] , see Figure 4 .

A recent prospective, randomized, parallel-group pharmacodynamic study ( PROTECT study) also showed that rabeprazole compared with famotidine even in clopidogrel-sensitive patients with a high incidence of drug interactions.
Does not reduce the efficacy of DAPT [16] , see Figure 4 .

Figure 4   Rabeprazole does not affect the efficacy of dual antiplatelet therapy in clopidogrel-sensitive population

Figure 4   Rabeprazole does not affect the efficacy of dual antiplatelet therapy in clopidogrel-sensitive population

Therefore, many guidelines believe that PPIs should still be combined for patients with high risk of gastrointestinal bleeding , but the influence of different PPIs on the antiplatelet effect of clopidogrel should be fully considered , and it is recommended that PPIs that do not affect the activity of P4502C19 , such as rabeprazole, are the first choice [1] ,2,11] .

Therefore, many guidelines believe that PPIs should still be combined for patients with high risk of gastrointestinal bleeding , but the influence of different PPIs on the antiplatelet effect of clopidogrel should be fully considered , and it is recommended that PPIs that do not affect the activity of P4502C19 , such as rabeprazole, are the first choice [1] ,2,11] .

Epilogue

Epilogue

Antiplatelet therapy (especially DAPT ) is of great significance for preventing thrombosis and reducing the occurrence of ischemic events after PCI .
The prevention of gastrointestinal bleeding through PPI is the escort for the safety of antiplatelet therapy .
The interaction between PPI and clopidogrel is not a class effect, and PPIs that do not affect CYP2C19 activity , such as rabeprazole , should be preferred .

Antiplatelet therapy (especially DAPT ) is of great significance for preventing thrombosis and reducing the occurrence of ischemic events after PCI .
The prevention of gastrointestinal bleeding through PPI is the escort for the safety of antiplatelet therapy .
The interaction between PPI and clopidogrel is not a class effect, and PPIs that do not affect CYP2C19 activity , such as rabeprazole , should be preferred .

references

references

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