Recommendations for antiplatelet therapy. European recommendations for dual antiplatelet therapy in patients
Held on August 26-30, 2017. A special update of the ESC position on dual antiplatelet therapy (DAPT) for coronary heart disease was presented for the first time at the annual congress of the European Society of Cardiology (ESC) in Barcelona (Spain). This document was developed jointly with the European Association of Cardiothoracic Surgeons (EACTS) and published online simultaneously in the European Heart Journal and on the ESC website. DAAT is a widely discussed topic on which there is a huge amount of somewhat conflicting information. This has led to considerable disagreement among practitioners, particularly regarding the optimal duration of DAPT after coronary artery stenting. Moreover, DAPT is one of the most intensively studied topics in the treatment of cardiovascular diseases. Research is underway to improve strategies for P2Y1,2 receptor inhibition and optimal treatment duration.
This document focuses on the use of DAPT in patients with coronary artery disease, and includes chapters covering DAPT after percutaneous coronary intervention (PCI), DAPT in the context of cardiac surgery, DAPT in patients with acute coronary syndromes (ACS) managed conservatively, DAPT in patients with indications for oral anticoagulants, elective noncardiac interventions in patients on DAPT, and DAPT in special patient populations, such as women, patients with diabetes, and patients with bleeding during treatment.
DAPT reduces the risk of stent thrombosis at any time after implantation - from acute to very late, and after myocardial infarction (MI) or PCI, it reduces the incidence of spontaneous MI. The risk of bleeding in patients receiving DAPT is proportional to its duration. The benefits of long-term DAPT, especially regarding mortality, depend on the previous history of cardiovascular disease (eg, history of prior ACS/MI or stable CAD). The new ESC document recommends the use of predictive models to assess the risk of bleeding with DAPT, and an individualized approach based on the risk of ischemic and bleeding events in each individual case.
The most controversial issue at the moment is the need for prolonged use of DAPT (more than 12 months) in patients with ACS who have undergone PCI. According to the authors of the document, this is a very difficult decision, which should be thought over more than once in order to achieve maximum benefits and minimize risks. In this situation, it is imperative to recognize that DAPT is a treatment regimen for the patient, not a stent, and it is possible that the medical community has not yet fully adapted to this paradigm. The ESC Working Group considers that the default duration of DAPT after ACS should be 12 months, regardless of the revascularization strategy chosen (i.e., medical therapy alone, PCI, or coronary artery bypass grafting). In patients at high risk of bleeding, this period should be reduced to six months. Extension of treatment beyond 12 months may be considered in those patients with ACS who tolerated DAPT well and did not have bleeding complications.
The document emphasizes that the presence of an indication for short-term DAPT should no longer be considered as a justification for the use of plain metal stents instead of the latest generation of drug-eluting stents. The duration of DAPT should be determined by the risk of ischemic events and bleeding in a particular patient, and not by the type of stent.
Regardless of the type of metal stent used, the duration of DAPT in patients with stable coronary artery disease should be from one to six months, depending on the risk of bleeding. A longer duration of DAPT may be considered in cases where the ischemic risk clearly outweighs the risk of hemorrhagic complications.
Currently, there is insufficient evidence to recommend DAPT in patients with stable coronary artery disease undergoing revascularization with coronary artery bypass grafting.
The addition of DAPT to oral anticoagulants leads to a 2-3-fold increase in the risk of hemorrhagic complications. Therefore, in such patients, the need for anticoagulation should be reconsidered and treatment should be continued only if there is a compelling indication, such as atrial fibrillation, mechanical prosthetic heart valves, or recent history of deep vein thrombosis or pulmonary embolism. Depending on the risk ratio of ischemic and hemorrhagic complications, triple therapy (DAPT + oral anticoagulant) should not be prescribed at all after the patient is discharged from the hospital, or its duration should not exceed six months.
Regarding the choice of a specific P2Y1,2 receptor inhibitor, clopidogrel should be used by default when performing PCI in patients with stable coronary artery disease, those with indications for oral anticoagulants, and patients with ACS who have contraindications to the use of ticagrelor or prasugrel. In contrast, in patients with ACS, unless contraindicated, the default use of ticagrelor or prasugrel should be used. The decision about when to start taking a P2Y1,2 inhibitor depends on both the specific drug and the clinical situation (stable CAD or ACS).
The type and duration of DAPT should not differ between men and women, and between patients with and without diabetes.
Transluminal balloon angioplasty (TLBA) and coronary artery stenting or percutaneous coronary intervention (PCI). Preparation for surgery, surgical technique, recommendations after surgery
How to prepare for coronary artery stenting surgery.
In cases of myocardial infarction and unstable angina, coronary artery stenting operations are performed on an emergency basis. For stable CAD, it is scheduled in advance, giving you time to prepare. The operation is performed in the X-ray operating room.
General principles include:
Last meal the evening before surgery.
The area where the catheter is installed (groin area or forearm) should be shaved.
The night before surgery, bowel cleansing is performed.
In the morning, stop taking medications.
Particular attention should be paid to the mandatory use of the following medications before surgery:
Aspirin
Aspirin reduces the incidence of ischemic complications after PCI. The minimum effective dose of aspirin for PCI has not been precisely defined, but an empirically adjusted dose of 80–325 mg at least 2 hours before surgery is traditionally recommended.
Technique of percutaneous coronary interventions.
Before the procedure Intravenous access is established, monitoring of vital functions is established (ECG, blood pressure measurements, respiratory rate and blood oxygen saturation), and a sedative is administered within 30 minutes. For the procedure, you lie on your back on the x-ray table. X-ray cameras can move over and around your head and chest and film from different positions. You will stay awake during surgery so that you can follow the instructions. The catheterization (puncture) area will be cleaned and disinfected, and you will then feel numb as the local anesthetic is administered. To perform stenting of the coronary arteries, transfemoral access (through the common femoral artery below the inguinal fold) or transradial access (through the radial artery of the forearm) is used.
After puncture of the artery, a guidewire is passed through the needle, through which a diagnostic catheter is passed, and the system is brought to the ascending aorta. Advancing the catheter should not cause pain, and you will not feel it move. Tell your doctor if you have discomfort. Then, under the control of fluoroscopy and injections of a contrast agent, selective coronary angiography of the narrowed coronary artery is started. The administration of a contrast agent may be accompanied by a brief sensation of warmth or redness. Through the same puncture hole, a special conductor is inserted, equipped with a balloon on which a stent is mounted in a compressed state, and under the control of an X-ray machine it is brought to the site of the narrowing of the vessel. Having reached the stenotic area of the coronary artery, the balloon inflates and presses the stent into the wall of the vessel, maintaining the increase in the lumen of the artery achieved by inflating the balloon. The balloon is then deflated and removed from the coronary artery along with the guidewire and catheter. The stent remains and maintains the lumen of the vessel. The correct placement of the stent is controlled by fluoroscopy during the administration of a contrast agent. Depending on the clinical situation, one or more stents may be required.
After surgery the catheter is removed from the groin or arm and a tight pressure bandage is applied. You are transferred to the department and prescribed bed rest in the supine position for several hours (in some cases up to a day) in order to prevent bleeding from the puncture site.
After the examination, the catheter is removed from the groin or arm and a tight pressure bandage is applied. You are transferred to the department and prescribed bed rest in the supine position for several hours (in some cases up to a day) in order to prevent bleeding from the puncture site. Cold is applied to the puncture site, then a weight is applied.
Drink plenty of fluids to help your body eliminate the contrast material injected during the test. If you feel hungry, ask your doctor when you can eat. Check with your doctor about when to restart taking your medications, especially if you are taking glucose-lowering medications.
Observation in the hospital after surgery from one day. Most patients can be safely discharged from the hospital within 24-48 hours after uncomplicated PCI.
After you are discharged, avoid strenuous activities and heavy physical work for several days. The puncture site will likely remain tense for some time. It may be slightly swollen and have slight bruising.
Contact your doctor if:
- You notice bleeding, new bruising or severe swelling in the area of puncture and catheter placement;
- You feel increasing pain or discomfort in the area of puncture and catheter installation;
- Redness and fever appeared in the area of puncture and catheter installation;
- The temperature or color of the leg/arm through which the procedure was performed has changed;
- You feel chest pain or shortness of breath.
The material was prepared by T.V. Zavalikhina.
Long-term antiplatelet and anticoagulant therapy has long proven its advantages in the prevention of thrombotic and thromboembolic complications. Thousands of cardiovascular patients around the world take antiplatelet drugs or oral anticoagulants for months or even years, depending on which strategy is preferable in a particular clinical situation.
However, the doctor often has to solve a difficult problem - what to do if the patient is equally prescribed both antiplatelet drugs and an oral anticoagulant? Can warfarin be added to the treatment regimen if the patient is already taking aspirin, clopidogrel, or a combination of both? Will such comprehensive antithrombotic therapy provide additional protection or will it be unjustified, or even dangerous due to an increased risk of bleeding?
Persons with combined cardiovascular pathology are more common than with any single disease. In this case, the patient may have strict indications for both long-term use of anticoagulants and long-term, if not permanent, antiplatelet therapy (and often in the form of a combination of two different drugs). Sometimes such complex clinical situations are specified in current practice guidelines, but more often you have to make a decision yourself, weighing the benefits and risks of such a fairly aggressive antiplatelet combination for a given patient. The current evidence base in this regard is replete with contradictions and blind spots: many studies indicate a significant increase in the risk of bleeding complications with a slight increase in effectiveness or no benefit of this combination, but there is also more optimistic data.
Relevance of combined antiplatelet therapy (antiplatelet drug + anticoagulant)
The practice of combined use of antiplatelet and anticoagulant drugs is quite common, being in demand by a wide variety of categories of patients. Moreover, every year the need for such an aggressive antiplatelet strategy for the management of cardiac patients increases. According to S.G. Johnson et al. (2007), approximately 4 out of 10 American patients taking warfarin also receive antiplatelet drugs (in most cases, acetylsalicylic acid (ASA), clopidogrel, dipyridamole, or a combination of ASA with clopidogrel or dipyridamole). The combination of antiplatelet therapy and warfarin is especially common in patients with heart failure, coronary heart disease (CHD), as well as in those who have had a stroke or transient ischemic attack (TIA).
The largest meta-analysis by the Antithrombotic Trialists' Collaboration, combining the results of 145 clinical trials, showed that the use of antiplatelet therapy in high-risk patients reduces the risk of cardiovascular events by 25%. Particularly significant benefits of antiplatelet therapy are observed in patients who have suffered acute coronary syndrome (ACS), as well as in those who have undergone coronary artery intervention, primarily with stent placement.
In addition, it has now been proven that for many categories of high-risk cardiovascular patients, long-term antiplatelet therapy is preferable in the form of a combination of two drugs with different mechanisms of action. To date, the most convincing evidence base is for the combination of ASA and clopidogrel - a number of large randomized studies have demonstrated that the use of such a combination is more effective than monotherapy with ASA, clopidogrel or any other antiplatelet agent, reduces the risk of ischemic events with comparable safety (CURE, CREDO , CHARISMA, CLARITY-TIMI 28, COMMIT/CCS-2). The benefits of dual antiplatelet therapy were especially pronounced in patients with ACS, as well as in patients after percutaneous coronary intervention (PCI) with the installation of coronary stents, therefore long-term use of a combination of ASA and clopidogrel is today a mandatory requirement for patients who have undergone ACS (both with ST elevation, and without it), especially in the case of PCI.
Along with this, many patients may also require short-term or rather long-term therapy with oral anticoagulants: this applies primarily to patients with atrial fibrillation, persons with valvular heart disease, mechanical prosthetic heart valves, mural thrombi of the left ventricle, as well as post-infarction patients with a high risk of developing intracardiac thrombus. The use of warfarin in such patients reliably and significantly reduces the risk of cardioembolic stroke. In addition, anticoagulants are indicated in the case of deep vein thrombosis of the lower extremities and other manifestations of venous thromboembolism - while taking warfarin in such patients, the risk of pulmonary embolism (PE) is significantly reduced.
Thus, for many cardiovascular patients, for a more or less long term, there is a need to combine antiplatelet therapy with oral anticoagulants. The issue of such combination has become especially relevant after recent updates to practical guidelines on the treatment of ACS. According to these guidelines, significant benefits of long-term antiplatelet therapy after coronary stenting have been proven, and the recommended duration of taking a combination of antiplatelet drugs (ASA and clopidogrel) has increased to a year in most patients with installed coronary stents. If it is necessary to prescribe warfarin against the background of such dual antiplatelet therapy, many doubts and questions arise.
According to the latest update of the European Society of Cardiology guidelines (2008), in case of a high risk of thromboembolic events, patients who have had an ST-segment elevation myocardial infarction can receive oral anticoagulants in combination with low-dose ASA (IIa, B), clopidogrel (IIb, C) or double antiplatelet therapy (ASA + clopidogrel) (IIb, C). The combination of warfarin and ASA is indicated for high risk of thromboembolism; a combination of warfarin and dual antiplatelet therapy - after stenting, if there are indications for taking oral anticoagulants; a combination of warfarin and clopidogrel - after stenting, if there are indications for taking oral anticoagulants, and there is a high risk of bleeding. However, what are the main benefits and risks of such treatment?
The problem of hemorrhagic complications of antiplatelet therapy is one of the most serious iatrogenic problems of modern medicine. In recent years, there have been increasing reports that hemorrhages caused by taking antiplatelet agents are one of the most common side effects of drug therapy. Many of these hemorrhagic complications are very serious, leading to acute cerebrovascular accidents, dangerous gastrointestinal bleeding, and fatal outcomes. Therefore, it is natural that the increasing aggressiveness of antiplatelet therapy, especially in the situation of combining several different antithrombotic drugs, becomes a stumbling block.
Nevertheless, there is reason to believe that after careful selection of patients for combination antiplatelet therapy, the use of combinations with maximum advantages in terms of the overall efficacy-safety indicator and subject to strict monitoring of hemostasis, the benefits of such treatment will be significantly higher than the possible risks.
Evidence base
ASA + warfarin
One of the first major works devoted to the study of the combination of ASA and warfarin was a meta-analysis by P. Loewen et al. (1998), who pooled data from 16 studies comparing this combination with warfarin monotherapy. This meta-analysis showed that long-term use of warfarin with chronic ASA therapy is fully justified in patients with mechanical prosthetic heart valves at high risk of thromboembolic complications. In addition, this strategy, according to P. Loewen et al., can also be used for the primary prevention of thromboembolism in people at high risk of developing coronary artery disease, although in this case the expected benefits are small. However, the authors could not confirm the advisability of using a combination of ASA and warfarin in patients suffering from coronary artery disease, atrial fibrillation, ischemic stroke or coronary artery bypass surgery - in these situations, the increasing risk of hemorrhagic complications could not be compensated by the advantages of such a combination in relation to the prevention of thromboembolism.
A number of subsequent studies have also demonstrated that combining long-term antiplatelet and anticoagulant therapy may significantly increase the risk of developing bleeding complications.
In a meta-analysis by R.J. Larson, E.S. Fisher (2004), which included 9 large studies that compared warfarin therapy with a combination of warfarin and ASA, showed clear advantages of combining two antiplatelet agents compared with warfarin monotherapy (additional reduction in the risk of thromboembolic events and overall mortality) in patients with mechanical prosthetic heart valves . For other categories of patients included in this meta-analysis (myocardial infarction or atrial fibrillation), such benefits could not be confirmed - the data obtained were contradictory, and differences between groups often could not reach statistically significant values.
According to the pharmacoeconomic analysis of S.G. Johnson et al. (2008), the risks associated with adding warfarin to antiplatelet drugs (ASA, clopidogrel and/or dipyridamole) outweighed the benefits. However, this study was retrospective, short-term (6 months), and examined the entire population of patients receiving the antiplatelet combination, regardless of underlying pathology and other factors that might influence the benefit/risk ratio.
In the randomized multicenter study WARIS II (M. Hurlen et al., 2002), which involved 3630 patients who had suffered a myocardial infarction, the combination of ASA with warfarin compared with ASA monotherapy resulted in a reduction in the incidence of major cardiovascular events (recurrent nonfatal infarction, thromboembolic stroke, death) – 15 vs 20% (p=0.001). However, the risk of hemorrhagic complications also increased in the combination treatment group (0.62 vs 0.17% for serious non-fatal hemorrhages, p<0,001).
In the same 2002, two more studies were completed comparing different strategies of antiplatelet therapy in patients who had suffered ACS - ASPECT-2 (R.F. van Es et al., 2002) and APRICOT-2 (M.A. Brouwer et al., 2002). Both studies showed that the use of a combination of ASA and an oral anticoagulant after ACS significantly reduced the risk of major ischemic events and death compared with ASA monotherapy. At the same time, the risk of hemorrhagic complications increased slightly and mainly due to small, harmless hemorrhages. In the APRICOT-2 study, the benefit of the combination was reflected in a reduced risk of reocclusion (15 vs 28% for TIMI ≤2, p<0,02; 9 vs 20% для TIMI 0-1, p<0,02), потребности в реваскуляризации (31 vs 13%, p<0,01), повторного инфаркта (8 vs 2%, p<0,05) и повышении выживаемости больных (86 vs 66%, p<0,01) на протяжении 3 мес после ОКС. В ASPECT-2 комбинация АСК и варфарина у пациентов, перенесших ОКС, привела к снижению частоты регистрации комбинированной конечной точки (инфаркт, инсульт или смерть) по сравнению с монотерапией АСК (5 vs 9%, p=0,03), хотя по сравнению с монотерапией варфарином достоверных различий не было.
Interesting results of the meta-analysis by F. Dentali et al. (2007), who combined the results of ten randomized clinical trials comparing the combination of ASA and warfarin with warfarin monotherapy. According to the results, the risk of thromboembolic complications in patients taking the combination of drugs was lower than in the warfarin monotherapy group, but these benefits were limited to the subgroup of patients with mechanical prosthetic heart valves. For other categories of patients (with atrial fibrillation or coronary artery disease), no differences were noted in the risk of thromboembolic complications and mortality. Moreover, the risk of serious hemorrhagic complications in the combination therapy group was higher than when taking warfarin alone. The benefits of using a combination of ASA and warfarin over warfarin monotherapy in patients undergoing heart valve replacement were previously shown in another meta-analysis by J.C. Cappelleri et al. (1995). According to these authors, the combination reduced the risk of thromboembolic complications by 67% and overall mortality by 40%, although an increase in the risk of hemorrhagic events was also noted.
Taking into account the data from these and other studies and meta-analyses, it was concluded that the combination of ASA and warfarin is preferable in patients with mechanical prosthetic heart valves.
In a large meta-analysis by F. Andreotti et al. (2006), which included the results of a 5-year observation of more than 10 thousand patients who had suffered ACS, the combination of ASA and an oral anticoagulant (INR 2-3) helped prevent 3 serious cardiovascular events per 100 patients, but at the same time caused 1 serious hemorrhagic complication per 100 patients (compared to ASA monotherapy). In this regard, experts from the European Society of Cardiology concluded that the combination of ASA and an oral anticoagulant may be a reasonable strategy in people who have had a ST-elevation infarction and are at high risk of thromboembolic events.
ASA + clopidogrel + warfarin
Unfortunately, to date there is little evidence comparing the benefits and risks of triple antiplatelet therapy with other strategies (ASA monotherapy, clopidogrel or warfarin, dual antiplatelet therapy, a combination of one antiplatelet drug and warfarin, etc.). According to A.J. Hermosillo and S.A. Spinler (2008), who performed a systematic review of the available evidence on this issue (from 1966 to March 2008), only 12 such studies were published in the Medline database, and only one of them was randomized (and open-label). Four of these 12 studies showed benefits of triple antiplatelet therapy without a clinically significant increase in the risk of hemorrhagic complications, but the remaining 8 studies showed a 3- to 6-fold increase in the risk of hemorrhage. In 6 of these 12 studies, the effect of treatment on ischemic events was not analyzed at all (only safety was studied).
For example, in a large retrospective cohort study, Y. Konstantino et al. (2006) the use of triple antiplatelet therapy (ASA + thienopyridine + warfarin) in patients with high-risk ACS did not lead to an increase in mortality (neither by the 30th day after ACS, nor six months later) compared with double antiplatelet therapy (aspirin + thienopyridine), despite a 4-fold increase in the risk of hemorrhagic complications in the triple combination group. In addition, in the dual therapy group there was a tendency towards an increase in the need of patients for revascularization in the first 30 days after ACS. Based on the study results, the authors concluded that triple antiplatelet therapy, when both an antiplatelet agent and an anticoagulant are indicated, may be justified in high-risk patients, given the lack of difference in mortality.
Similar conclusions were drawn from the results of a study by A. Porter et al. (2006) for patients undergoing PCI. Unfortunately, this study did not have a control group, but the available data made it possible to judge that the benefits of triple antiplatelet therapy in such patients are not accompanied by a significant increase in the risk of hemorrhagic complications.
In a study by M.C. Nguyen et al. (2007) the addition of warfarin to antiplatelet drugs (ASA, clopidogrel, or their combination) in patients with ACS who underwent PCI did not lead to a significant increase in hemorrhagic complications over a 6-month follow-up, and in patients with atrial fibrillation, triple antiplatelet therapy provided additional benefits in regarding stroke prevention. The same group of authors in a study based on a post hoc analysis of data from the EXTRACT-TIMI 25 trial in the same year showed that triple antiplatelet therapy can be quite safe in patients who have undergone ST-segment elevation ACS, including after PCI.
Finally, in a recent study by J. Ruiz-Nodar et al. (2008) demonstrated that triple antiplatelet therapy is preferable in patients with atrial fibrillation who require PCI, provided that the risk of hemorrhagic complications is initially low. The results obtained indicate that the addition of warfarin to dual antiplatelet therapy (ASA + clopidogrel) in such patients significantly reduces both the incidence of the combined endpoint (death, heart attack, need for revascularization) and overall mortality, while the risk of serious hemorrhagic complications in such a triple combination did not increase significantly. This is the largest study to date examining the effect of triple antiplatelet therapy on both thromboembolic events and bleeding complications.
However, in most studies, the addition of warfarin to dual antiplatelet therapy (ASA + thienopyridine) was associated with a significant increase in the risk of bleeding complications - 3-6 times. The advantages of such an aggressive antiplatelet combination over dual antiplatelet therapy according to different studies are contradictory - they are either absent or not so significant that the increased risk of hemorrhage can be neglected.
Thus, in a population study by K. Buresly et al. (2005) analyzed data from more than 20 thousand elderly patients who had suffered a myocardial infarction. At the same time, the authors compared the risk of developing hemorrhagic complications in those who took ASA, warfarin, ASA + thienopyridine, ASA + warfarin or ASA + thienopyridine + warfarin. It turned out that the risk of hemorrhages while taking combination therapy increased slightly, but overall remained low. If in the ASA monotherapy group the risk of hemorrhagic complications requiring hospitalization was 0.03 cases per patient-year, then in the ASA and thienopyridine combination group it reached 0.07, in the ASA and warfarin combination group – 0.08, in the triple antiplatelet group therapy – 0.09 (1 out of 141 patients).
In a study by Z. Khurram et al. (2006) the addition of warfarin to dual antiplatelet therapy with ASA and clopidogrel increased the risk of hemorrhagic complications in patients undergoing PCI by 5 times. Another small study by D. DeEugenio et al. (2007) in the same category of patients, it was confirmed that the addition of warfarin to dual antiplatelet therapy is an independent risk factor for the development of serious hemorrhagic complications, and therefore the authors expressed the opinion that the strategy of triple antiplatelet therapy in patients with a low risk of thromboembolic events, most likely not advisable. In a study by P.P. Karjalainen et al. (2007) analyzed the differences between different strategies of long-term antiplatelet therapy for patients undergoing PCI: ASA monotherapy, clopidogrel or warfarin, combinations of ASA + clopidogrel, ASA + warfarin, clopidogrel + warfarin, ASA + clopidogrel + warfarin. The addition of warfarin did not appear to affect the primary endpoint (death + infarction + need for revascularization + stent thrombosis at hospital discharge), but was associated with an increased risk of thromboembolic events after a year of taking the combination compared with treatment regimens without warfarin. At the same time, the risk of serious hemorrhagic complications during the use of warfarin-containing combinations increased 3 times. The authors concluded that the long-term prognosis of most patients taking warfarin-containing antiplatelet combinations after PCI is unfavorable, regardless of the nature of the combination.
The only randomized prospective trial comparing dual and triple antiplatelet strategies was WAVE (S. Anand et al., 2007). For patients with obliterating atherosclerosis of the arteries of the lower extremities who underwent ACS or PCI, the authors also found no benefit from the addition of warfarin to dual antiplatelet therapy in terms of the effect on major thromboembolic events (heart attack, stroke, cardiovascular death, severe ischemia of peripheral or coronary arteries with the need immediate intervention). Along with this, triple antiplatelet therapy caused a significant increase in the risk of hemorrhagic complications compared with dual antiplatelet therapy.
Thus, today there is very little evidence on the possibilities of using triple antiplatelet therapy; it was obtained in heterogeneous studies, each of which had a number of limitations, and therefore is very contradictory and does not give a clear answer to the question of the advisability of combining dual antiplatelet therapy and warfarin . Based on these data, it is not yet possible to determine the most appropriate indication for such aggressive antiplatelet treatment, but there is reason to believe that, perhaps, after appropriate randomized trials, it can be found to be quite effective and safe for patients at high risk of thromboembolic complications, such as those with atrial fibrillation. arrhythmia and ACS, especially for those who are indicated for PCI. However, it seems that for the majority of patients with ACS, the most rational option remains the use of dual antiplatelet therapy - along with increased effectiveness in the prevention of ischemic events, such a strategy in high-risk patients does not significantly affect the incidence of serious hemorrhagic complications, unlike warfarin-containing combinations.
Currently, there are clear practical recommendations for the use of dual antiplatelet therapy. According to the latest updates of European and American recommendations for the management of patients with ACS with and without ST-segment elevation, the combination of ASA and clopidogrel is the most popular in the practice of managing cardiovascular patients, being indicated both in the conservative treatment of ACS (with or without thrombolysis), and in the case of PCI. Depending on the clinical situation, dual antiplatelet therapy can be used from 2 weeks (with a high risk of hemorrhagic complications) to 1 year; As for longer periods, the evidence base does not yet provide clear answers. The use of this combination is not indicated in patients who have suffered a stroke or TIA; in this situation, monotherapy with ASA or clopidogrel or a combination of ASA and modified-release dipyridamole is more preferable.
More aggressive antiplatelet therapy (antiplatelet agents + oral anticoagulant) may be warranted in patients at high risk of thrombosis and thromboembolic events. This primarily applies to people suffering from coronary artery disease, those who have undergone heart valve replacement or coronary artery stenting, as well as those who have had a stroke or TIA.
Experts have concluded that cautious use of combination antiplatelet therapy (warfarin with ASA, clopidogrel, or a combination of both) may be recommended when the risk of thromboembolism is high and there are indications for both antiplatelet agents and oral anticoagulants (eg, atrial fibrillation and/or the presence of a thrombus in the cavities of the left heart in persons who have undergone ACS or PCI in patients with mechanical prosthetic heart valves, especially with an increased risk of thromboembolism, etc). But it must be indicated that such therapy is associated with an increased risk of hemorrhagic complications. The doctor must carefully weigh the benefits and risks of such treatment before making a decision. In such patients, the international normalized ratio should be strictly kept at 2.0-2.5 (predominantly), 2.0-3.0 or 2.5-3.5 depending on the clinical situation, and the doses of drugs used should be minimal . Similar recommendations are given in the ACC/AHA guidelines for the management of patients with ACS with ST-segment elevation (2007) and without ST-segment elevation (2007), the ACC/AHA/SCAI guideline for PCI (2007), the ESC guideline for the management of patients with non-ST segment elevation ACS ST (2007) and other advisory documents of international importance. Special precautions should be taken in relation to elderly patients and persons with risk factors for hemorrhagic complications.
In particular, the European Society of Cardiology guidelines for the management of patients with ST-segment elevation myocardial infarction (2008) note that due to the lack of evidence obtained in prospective randomized trials, it is currently impossible to give clear recommendations on the indications for the use of triple antiplatelet therapy, but believe that its feasibility should be considered in patients who have undergone coronary artery stenting for ST-segment elevation MI and at the same time have indications for oral anticoagulation (for example, atrial fibrillation). If the risk of hemorrhagic complications in such patients is high, it is preferable to use only an oral anticoagulant with a short course of antiplatelet therapy with clopidogrel alone.
In addition, many experts note that the level of hemorrhagic complications while taking warfarin (in combination with or without antiplatelet drugs) largely depends on the effectiveness of the surveillance system for patients taking this anticoagulant for a long time, and is minimal with well-established anticoagulant clinics with careful monitoring the state of hemostasis. Therefore, future studies addressing this issue should also consider the intensity of such monitoring and the severity of hemostasis control in patients taking warfarin in addition to antiplatelet agents.
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9. Van de Werf F., Bax J., Betriu A. et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology. Eur Heart J 2008; 29: 2909-2945.
Scientific and practical medical journal.
Coronary artery stents are widely used to treat coronary artery disease in all its manifestations, from stable angina to myocardial infarction. Coronary stent placement has become a routine medical procedure performed on millions of patients every year. Metallic and drug-eluting stents are commonly used. Although drug-eluting stents demonstrate fewer short- and mid-term vascular complications, there are concerns regarding long-term prognosis.
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To prevent vascular complications (thrombosis), dual antiplatelet therapy (eg, aspirin and clopidogrel) is used as an important part of the patient's treatment after stent placement. To prevent in-stent thrombosis of a drug-eluting stent, longer antiplatelet therapy is required than after installation of a metal stent. Unfortunately, antithrombotic therapy is associated with an increased risk of bleeding, which can range from minor to life-threatening. This is partly due to the long-term effects of antiplatelet agents, partly because bleeding and atherosclerosis have many common risk factors. When taking antiplatelet drugs, bleeding can develop both at the site of penetration into the large vessel for stenting, and in other organs, for example, intracranial vessels or the gastrointestinal tract.
What is a coronary stent?
Coronary disease (coronary heart disease) can be treated by influencing the factors that cause coronary atherosclerosis (smoking cessation, normalizing blood pressure, lowering cholesterol) with antiplatelet drugs, but in many cases it also requires operations to restore the patency of the coronary arteries. Such operations include coronary angioplasty and coronary artery bypass surgery. Coronary angioplasty is less traumatic than bypass surgery and can be performed with or without stent placement. Stents are devices that are folded through special conductors to the site of narrowing of the coronary artery and are straightened in this place, serving as a framework for the vessel, which in most cases does not allow the narrowing to occur again.
Coronary stents are divided into two broad categories:
- stents of the first generation - metal without coating,
- second generation stents – drug-eluting.
The main complication after stent placement is restenosis (re-narrowing of the coronary artery), which may require other procedures to restore blood flow. Restenosis causes the proliferation of cells in the inner layer of the vessel and muscle cells of the vessel wall, which, together with the thrombus that appears here, can completely block the vessel. Drug-eluting stents that release substances that prevent cell proliferation, such as sirolimus, tacrolimus, paclitaxel, and zotarolimus, developed and introduced in the last decade, reduce the likelihood of restenosis.
What are the indications for antiplatelet therapy after stenting?
During coronary artery intervention, a wide range of antithrombotic agents are used, such as heparin, glycoprotein IIb/IIa inhibitors, and direct thrombin inhibitors. For acute and long-term treatment of myocardial infarction and unstable angina, aspirin is used in conjunction with other antiplatelet drugs. such as clopidogrel, reducing the risk of complications. Moreover, in patients with coronary stents, dual antiplatelet therapy is prescribed to reduce the risk of stent thrombosis and restenosis. This treatment is prescribed for different periods of time, depending on the type and sometimes location of the coronary artery lesion. Due to the risk of late in-stent stenosis when using drug-eluting stents, special attention is paid to the use of dual antiplatelet therapy in patients with such stents. For them, treatment continues for a year.
Bleeding from a vessel at the access site after stenting
Vascular access for angioplasty can be femoral (upper thigh), radial (wrist), or brachial (rare). Complications at the access site occur in 2–6% of cases and include hematoma and pseudoaneurysm. formation of an arteriovenous fistula, ischemia of the lower limb (with femoral access), infection and retroperitoneal bleeding. Minor bruises and hematomas are common and resolve after some time without special treatment. Large bruises indicate the formation of a large hematoma or other complications and require examination (ultrasound diagnostics). Large hematomas may require surgical treatment.
Retroperitoneal bleeding may occur when the femoral artery is used for access, although this complication occurs in less than 1% of cases. Blood entering the peritoneum can cause severe pain in the abdomen or back, accompanied (if not recognized at the time) by a decrease in blood pressure. Treatment of major retroperitoneal bleeding is often conservative with replacement of lost fluid and careful monitoring of important vital signs. In some cases, surgery is required.
Intracranial bleeding after stenting
Intracranial bleeding is one of the most severe complications of antiplatelet therapy. With such bleeding, mortality and disability are high. Concomitant factors such as high blood pressure, excess alcohol consumption, male gender, advanced age, and smoking increase the likelihood of bleeding.
Although intracranial bleeding is uncommon, the physician must be alert when working with patients after stent placement and respond quickly if neurological symptoms occur. Treatment of intracranial bleeding is carried out by neurosurgeons in a hospital setting. Such bleeding most often requires discontinuation of antiplatelet agents, although further treatment is carried out in close contact with cardiologists.
Bleeding from the gastrointestinal tract after stenting
The risk of gastrointestinal bleeding is increased in individuals taking antiplatelet agents. Concomitant diseases also play a major role. Bleeding can start in any part of the gastrointestinal tract, with bleeding from the upper digestive tract being most common. In patients, as a rule. vomiting of fresh or altered blood develops or a specific stool occurs, characteristic of the flow of blood into the intestines. Pain in the upper abdomen is common. However, atypical cases are also possible when bleeding is manifested by symptoms of acute loss of circulating blood volume, angina pectoris, and dizziness when moving to a vertical position.
Factors contributing to bleeding in patients receiving dual antiplatelet therapy have been well studied. These include a history of peptic ulcer disease, advanced age, male gender, concomitant use of anticoagulants, steroids or non-steroidal anti-inflammatory drugs, Helicobacter pylori infection, pre-existing anemia, diabetes and smoking.
Can using clopidogrel with proton pump inhibitors reduce the risk of bleeding?
Current guidelines recommend prescribing proton pump inhibitors to patients at high risk for gastrointestinal bleeding and receiving dual antiplatelet therapy. In the recent past, there has been suspicion of decreased effectiveness of clopidogrel taken in conjunction with proton pump blockers. However, recent research has established. that the interaction of these drugs is minimal.
How is acute bleeding from the gastrointestinal tract treated?
Work with such patients is carried out in a specialized medical institution where endoscopists can work with the patient and there is a surgical team. Treatment begins with the introduction of blood substitute fluids into the bloodstream. It is possible to use components of donor blood. Laboratory tests are performed, including a general blood test, a study of the hemostasis system, a biochemical study, and determination of the blood group.
What is the role of blood transfusion?
The purpose of blood transfusion is to correct global and local oxygen supply to tissues and improve hemostasis (correction of blood clotting disorders). This treatment is prescribed when there is a loss of about 30% of the circulating blood volume, which is determined by special calculations.
When is endoscopy of the gastrointestinal tract performed?
Such a study should be performed no later than 24 hours after the discovery of bleeding, however, in patients with active bleeding and violation of vital signs, this should be performed urgently. Studies have shown that endoscopy can be safely performed early after acute coronary syndrome.
Should antiplatelet drugs be discontinued after major bleeding occurs after stenting?
After the bleeding has stopped, it is necessary to evaluate the possibilities of preventing its recurrence. The use of non-steroidal anti-inflammatory drugs is canceled and eradication (elimination in the body) of Helicobacter pylori is carried out. Although many doctors intuitively strive to discontinue antiplatelet drugs. However, stopping their use is fraught with stent thrombosis. Therefore, within five days after the bleeding has stopped (confirmed by endoscopy), it is advisable to resume antiplatelet therapy under the cover of proton pump blockers. In some cases, aspirin is stopped, but clopidogrel is continued, as a drug that is safer for the gastrointestinal tract. Treatment of a patient with a freshly placed coronary stent and gastrointestinal bleeding is a balance between the risk of bleeding and the risk of stent thrombosis. Therefore, the final decision on treatment tactics is made individually.
Three-component antithrombotic therapy after stenting
Research into the use of dual antiplatelet therapy after stent placement is actively ongoing. The most difficult issue is the implementation of such treatment in patients with an artificial heart valve and atrial fibrillation, since they are already receiving anticoagulants and their antithrombotic therapy becomes triple, which significantly increases the risk of bleeding.
Our comment
Unfortunately, complications after stenting are quite possible. Therefore, everyone who has undergone stenting should be aware of them in order to:
- strictly adhere to medical prescriptions, which helps maintain a balance of risks,
- seek help in time if bleeding begins
The leading cause of mortality worldwide is still cardiovascular disease, despite the high level of development of cardiology over the past decades. The various clinical manifestations of vascular pathology are based on a common anatomical substrate in the form of dysfunction of the arterial endothelium, chronic inflammation and damage to the cap of the atherosclerotic plaque, slowing of blood flow, and the formation of an intravascular thrombus. In this regard, reducing the risk of developing thrombotic complications is the main task that a doctor who wants to increase the duration and improve the quality of life of patients with cardiovascular diseases should set.
The pathogenesis of thrombosis includes three main points for drug action: platelet link - the action of antiplatelet agents, the coagulation system - the zone of action of anticoagulants, fibrin - the action of fibrinolytics. Platelets are the first to respond to the rupture of an atherosclerotic plaque, launching a coagulation cascade; they are a source of active synthesis of humoral factors that simultaneously stimulate the processes of thrombus formation and inflammation. According to a meta-analysis of 287 randomized studies on secondary prevention and 6 studies on primary prevention, the use of antiplatelet therapy can reduce the risk of non-fatal myocardial infarction and non-fatal cerebral infarction by 23%. This meta-analysis confirms that the leading role in the prevention of complications of atherosclerosis should be given to antiplatelet agents.
Antiplatelet agents are medications that prevent thrombosis by reducing the functional activity of platelets. To date, more than 20 different drugs are known that can inhibit platelet function through various mechanisms of action. However, during many years of practice and clinical studies, effectiveness was confirmed only for cyclooxygenase inhibitors (acetylsalicylic acid), adenosine diphosphate (ADP) receptor blockers - P2Y12 (clopidogrel, prasugrel, ticagrelor), phosphodiesterase inhibitors (dipyridamole) and glycoprotein IIb-IIIa antagonists for intravenous use (abciximab, tirofiban, eptifibatide). Activation of platelets and their subsequent aggregation occur under the influence of various mediators, the most important of which are thromboxane A2 and ADP, therefore acetylsalicylic acid (ASA) and ADP inhibitors (clopidogrel, prasugrel, ticagrelor) are most widely used.
The history of the creation of the class began with the discovery of the antiplatelet properties of ASA. In 1987, the first randomized Canadian trial was published involving 585 stroke patients treated with ASA for 26 months. The study demonstrated the effectiveness of ASA against recurrent stroke. This was the reason that in 1980, the US Food and Drug Administration (FDA) approved ASA for the treatment of patients after stroke. Subsequently, the effectiveness of ASA in reducing the risk of death and recurrent myocardial infarction in patients with unstable angina and non-ST segment elevation myocardial infarction was proven. Thus began the era of antiplatelet therapy and its first worthy representative - acetylsalicylic acid.
Acetylsalicylic acid blocks platelet activation by inhibiting cyclooxygenase (COX), preventing the formation of thromboxane A2. Platelets are anucleate cells, so they lack the ability to synthesize proteins. Irreversible inhibition of COX-1, the impossibility of its resynthesis due to the absence of a nucleus, as well as the daily renewal of the platelet pool by only 10% lead to the fact that the blockade of thromboxane synthesis during ASA therapy persists throughout the platelet life span, up to 10 days. Complete suppression of thromboxane production is achieved with constant long-term administration of ASA in doses ≥ 75 mg/day. In most patients with stable coronary heart disease (CHD), low-dose ASA is preferable due to its favorable benefit-risk ratio. ASA for this category of patients remains the basis for drug prevention of arterial thrombosis. The damaging effect of ASA on the gastrointestinal tract (GIT) increases as the dose increases. The drug is recommended for all patients with an established diagnosis of coronary artery disease without any restrictions on the duration of use. The optimal benefit-risk ratio is achieved when using ASA in a dose range from 75 to 150 mg/day; when used as part of dual antiplatelet therapy, the dose is 75-100 mg.
However, in recent years, the problem of resistance to ASA therapy has been actively discussed, which is understood as the inability of the drug in some patients to adequately suppress platelet function, reduce the synthesis of thromboxane A2 and/or prolong bleeding time. The prevalence of resistance to ASA therapy, according to various studies, ranges from 10% to 45%. Among the possible reasons for this phenomenon are the following:
- pharmacodynamic interactions of ASA with non-steroidal anti-inflammatory drugs (NSAIDs);
- the presence of non-platelet sources of thromboxane A2 synthesis;
- expression of COX-2 in newly formed platelets;
- hydrolysis of ASA by esterases of the gastrointestinal mucosa;
- increased synthesis of thromboxane A2;
- hyperlipidemia;
- genetic features.
A number of independent studies have found that in patients with acute coronary syndrome (ACS) without ST-segment elevation (ESSENCE, PRISM PLUS), the immediate prognosis depends on previous use of ASA before the development of exacerbation of coronary artery disease. Thus, in the PRISM PLUS study, when using ASA for ACS, the incidence of myocardial infarction, refractory angina and sudden death by the 7th day of observation was 12.1% among patients who had not previously taken ASA, and 23.5% among those taking ASA before the development of an exacerbation. This fact was called the “aspirin paradox,” which led D. L. Bhatt and E. J. Topol (2004) to classify ASA as “suboptimal antiplatelet agents.” All this contributed to the development and study of new antiplatelet drugs-ADP P2Y12 receptor inhibitors and the identification of approaches to dual antiplatelet therapy.
The group of ADP-P2Y12 receptor blockers includes the drugs ticlopidine, clopidogrel, prasugrel, and ticaglerol. These drugs inhibit platelet aggregation induced by adenosine diphosphate by causing changes in the platelet ADP receptor, which is called P2Y12. There are significant differences between the drugs listed above, for example, irreversible inhibitors of P2Y12 receptors include thienopyridines (ticlopidine, clopidogrel and prasugrel), and reversible inhibitors include triazolopyridines (ticagrelor). Comparative characteristics of the drugs are presented in table. 1.
Clopidogrel is the most well-known and actively used antiplatelet agent in Russian medicine today after ASA. The results of large clinical trials have proven the effectiveness of reducing the incidence of complications in a wide range of patients with coronary artery disease when adding clopidogrel to ASA, which served as the basis for the development of indications for dual antiplatelet therapy in patients with ACS without ST elevation, as well as after coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) to prevent thrombosis.
Clopidogrel, as can be seen from the table, is a prodrug; the drug has a complex metabolism. The absorption of clopidogrel in the intestine is controlled by a special protein (P-glycoprotein), encoded by the ABCB1 gene, in this regard, only about 15% of the absorbed clopidogrel in the liver is converted into an active metabolite. The process is two-step (oxidation and hydrolysis), depending on several isoenzymes of the cytochrome P450 system, the most important of which are CYP2C19 and CYP3A4. Despite the wide evidence base for the effectiveness of this drug, clopidogrel has a number of disadvantages, which include a delayed antiplatelet effect, since it is a prodrug and requires time to activate; maximum suppression of ADP receptors occurs only on the 4-5th day of regular use. In addition, there is variability in the antithrombotic effect of clopidogrel in different patients, which may be due to a number of pharmacokinetic factors, including insufficient loading and maintenance doses of the drug, impaired absorption and formation of the active metabolite, drug interactions, in particular with proton pump inhibitors, which are often prescribed to prevent bleeding from the upper gastrointestinal tract.
Due to the existing shortcomings of clopidogrel and the inability to solve this problem, the need to create a new drug from the group of ADP receptor blockers - P2Y12 - became obvious to the world community.
A new antiplatelet drug is ticagrelor, a direct-acting reversible antagonist of P2Y12 receptors. The drug is an active substance that is metabolized via the CYP3A4 isoenzyme to form an active metabolite. The degree of inhibition of P2Y12 receptors is determined primarily by the plasma levels of ticagrelor and, to a lesser extent, its active metabolite. The half-life is about 12 hours, and therefore the drug is prescribed twice a day. Ticagrelor is characterized by a faster onset of therapeutic action and provides a more pronounced and persistent inhibition of platelet activation compared to clopidogrel. At the same time, recovery of platelet function after discontinuation of ticagrelor occurs faster compared to clopidogrel. The presence of more attractive pharmacological properties, as well as the existing problems associated with taking clopidogrel, were the main reasons for organizing the large-scale PLATO (Platelet inhibition and patient outcomes) study, which compared the effectiveness and safety of ticagrelor compared with clopidogrel in patients with ACS. According to a study published on August 30, 2009 at the Congress of the European Society of Cardiology (ESC), the new antithrombotic drug ticagrelor is more effective than clopidogrel in treating patients with acute coronary syndrome and does not increase the risk of bleeding.
Researchers led by Lars Wallentin randomized 18,624 patients with ACS hospitalized between 2006 and 2008 at 862 hospitals included in the PLATO trial. Patients were divided into 2 groups: in the first group patients received ticagrelor (180 mg loading dose and 90 mg twice a day), in the other - clopidogrel (300 or 600 mg loading dose and 75 mg daily). All patients also took ASA at a dose of 75-100 mg. The groups were carefully balanced taking into account baseline clinical parameters, concomitant diseases and treatment tactics. 37.5% of patients had acute myocardial infarction with ST segment elevation, 42.9% had acute myocardial infarction without ST segment elevation, and 16.6% had unstable angina. The duration of medication use ranged from 6 to 12 months, with an average of 277 days. The results showed that during therapy with ticagrelor compared with clopidogrel, there was a significant reduction in the total number of primary endpoints (cardiovascular death, myocardial infarction or stroke): 9.8% versus 11.7%, a risk reduction of 16%, p< 0,001. У получавших тикагрелор, по сравнению с лечившимися клопидогрелом, отмечалось достоверное снижение частоты развития инфаркта миокарда: с 6,9% до 5,8%, сердечно-сосудистой смерти — с 5,1% до 4%. В то же время общее число перенесенных инсультов было одинаковым в обеих подгруппах: 1,5% и 1,3%. Частота комбинированной вторичной конечной точки (смерть от сосудистых причин, инфаркт миокарда, инсульт, рецидивирующая ишемия миокарда, транзиторная ишемическая атака или другие варианты артериального тромбоза), а также смерти от всех причин были достоверно ниже в группе тикагрелора по сравнению с клопидогрелом: 14,6% против 16,7% и 4,5% против 5,9% соответственно. Не было выявлено значимых различий между группами в частоте больших, а также фатальных и угрожающих жизни кровотечений. Интересно отметить, что риск больших кровотечений, включая фатальные внутричерепные, не связанных с процедурой АКШ, был несколько выше в группе тикагрелора по сравнению с клопидогрелом (4,5% против 3,8%, p = 0,03). В то же время количество связанных с АКШ кровотечений было меньше среди лиц, получавших тикагрелор (7,4% против 7,9%) .
The results of 13,408 (72%) patients with an invasive treatment strategy planned at the randomization stage were analyzed separately. 49.1% of patients were diagnosed with acute coronary syndrome with ST segment elevation on electrocardiography (ECG) and 50.9% with acute coronary syndrome without ST segment elevation on ECG. During the first hospitalization, PCI was performed in 10,298 (72%) patients and CABG in 782 (5.8%). The average time to PCI was 2.4 (0.8-20.1) hours after randomization in patients with ACS without ST-segment elevation on the ECG and 0.5 (0.2-1) hours in patients with ACS with ST-segment elevation on the ECG . The average time to CABG was 6 (3-10) days. The total number of myocardial infarctions, strokes and cases of cardiovascular death during therapy with ticagrelor decreased to 9% (clopidogrel - by 10.7%), i.e. the risk reduction was 16%, p< 0,0025.
It is important to emphasize that the benefit of ticagrelor on the primary endpoint was observed across different subgroups and was independent of the clopidogrel loading dose. Major bleeding was equally common in those treated with ticagrelor and those treated with clopidogrel (11.6% vs. 11.5%). The incidence of stent thrombosis was significantly lower in the ticagrelor group, both with and without drug-eluting stents. The incidence of certain stent thrombosis in patients receiving ticagrelor was significantly lower at both 30 days and 360 days of follow-up compared with those treated with clopidogrel, including those patients taking a loading dose of 600 mg or more.
When analyzing a portion of the study that included 1261 patients undergoing CABG within 7 days of the last study drug dose, there was no significant difference in the reduction in the number of primary endpoints (10.6% in the ticagrelor group and 13.1% in the clopidogrel group). At the same time, among those taking ticagrelor, there was a significant decrease in overall mortality by 51%, and cardiovascular mortality by 48%, both in the early and late periods after surgery.
Thus, PLATO was the first large-scale study to demonstrate the clinical effectiveness of ticagrelor in reducing the incidence of major vascular events in patients with ACS, without a significant increase in the risk of bleeding. A more significant reduction in the risk of thrombotic episodes during therapy with ticagrelor appears to be due to more rapid and intense inhibition of platelet P2Y12 receptors. When a loading dose of 600 mg of clopidogrel is prescribed, it takes 2-4 hours to achieve 50% inhibition of platelet aggregation, and the same effect is achieved after 30 minutes when taking 180 mg of ticagrelor. In addition, there is a fairly large group of patients with the presence of defective variants of alleles of the cytochrome P450 system, which is associated with a slowdown in the formation of the active metabolite of clopidogrel, insufficient suppression of platelet function when taking it, as well as with a higher risk of cardiovascular complications after acute coronary syndrome and during PCI. The advantages of ticagrelor also include the reversible nature of inhibition of platelet P2Y12 receptors, which means a more rapid cessation of the antiplatelet effect after discontinuation of the drug. This circumstance seems important during invasive interventions, as well as before the upcoming CABG procedure. Although the incidence of major bleeding was no lower with ticagrelor than with clopidogrel, it should be noted that the greater inhibition of platelet function was not associated with an increase in the incidence of major bleeding. This compares favorably with prasugrel, whose more pronounced antiplatelet effect is accompanied by an increased risk of major bleeding.
The European Society of Cardiology recommended the use of ticagrelor (at a loading dose of 180 mg and 90 mg 2 times a day - in maintenance) to all patients with ACS, regardless of the planned treatment strategy (invasive or conservative) as first-line therapy. If patients received clopidogrel at the very beginning of the disease, it should be replaced with ticagrelor. Taking clopidogrel in patients with ACS with invasive or conservative strategies is possible only in cases of absence or intolerance to ticagrelor or prasugrel. The duration of therapy with P2Y12 receptor inhibitors in patients who have suffered acute coronary syndrome is 12 months. In patients on therapy with P2Y12 receptor inhibitors, in cases of planned surgery (including CABG), ticagrelor and clopidogrel are canceled 5 days before, and prasugrel 7 days before. Dual antiplatelet therapy is mandatory while taking ASA at a dose of 75-100 mg/day. The use of dual antiplatelet therapy in stable coronary artery disease could provide more effective prevention of coronary thrombosis. However, in the CHARISMA study, which included stable patients with atherosclerotic lesions of various vascular territories or multiple cardiovascular risk factors, the addition of clopidogrel to ASA did not bring additional benefit. The 2013 European Society of Cardiology guidelines indicate that dual antiplatelet therapy is beneficial only in certain categories of patients at high risk of ischemic events. Routine administration of this therapy to patients with stable coronary artery disease is not recommended.
Thus, atherothrombosis is the cause of high mortality in patients with cardiovascular diseases throughout the world. One of the key points of therapy is the competent prescription of antiplatelet drugs. The main effective oral drugs prescribed in clinical practice are ASA, clopidogrel, ticagrelor, prasugrel. In table Figure 2 presents an algorithm for selecting antiplatelet agents. Modern cardiology is actively developing, and one can hope that new facets of known drugs and the development of new ones will help doctors in the daily fight against cardiovascular diseases.
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G. I. Nechaeva 1, Doctor of Medical Sciences, Professor
O. V. Drokina,Candidate of Medical Sciences
N. I. Fisun, Candidate of Medical Sciences
State Budgetary Educational Institution of Higher Professional Education Omsk State Medical Academy of the Ministry of Health of the Russian Federation, Omsk
* The drug is not registered in the Russian Federation.
