A REVIEW ON CLINICAL APPLICATION OF CLOPIDOGREL IN ACUTE CORONARY SYNDROME

ABOUT AUTHORS:
Tripti Verma*, Keshav Vashistha, Sachin Vispute
B N College of Pharmacy,
Udaipur, Rajasthan
*triptiphsoni22@gmail.com

ABSTRACT:
The review examines the recent trials of clopidogrel in the treatment of acute coronary syndromes, as well as current cardiac guidelines from several professional societies. As the publication of the landmark study Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE), the clinical benefit of early and intermediate-term use of combined antiplatelet agents--clopidogrel plus aspirin--in non-ST-segment elevation myocardial infarction (NSTEMI) patients became evident. Pretreatment and intermediate-term therapy with clopidogrel in NSTEMI ACS patients undergoing percutaneous coronary intervention (PCI) was further supported by the PCI-CURE trial. Recently, the results of two major trials Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction 28, Clopidogrel and Metoprolol in Myocardial Infarction Trial established the pivotal role of clopidogrel in the other spectrum of ACS-STEMI. Coupled with the results from previous multicentre trials, these two studies provide a guide for the early and long-term use of clopidogrel in the whole spectrum of ACS. A review summarising the results of the recent clinical trials and a discussion on its implications for the clinical management of ACS is presented.Clopidogrel is well established in the treatment of acute coronary syndromes and is ubiquitous in cardiology practice. Landmark studies have established the importance of clopidogrel in the treatment of non-ST and ST elevation myocardial infarction and in percutaneous coronary intervention by reducing death, reinfarction, and adverse cardiac events.

REFERENCE ID: PHARMATUTOR-ART-1789

INTRODUCTION:
Clopidogrel inhibits platelet activation through the adenosine diphosphate pathway. Because it blocks platelet activation via a different route than aspirin does, combination therapy with aspirin may offer benefits over either drug alone. Clopidogrel has been shown to be superior to aspirin in the secondary prevention of vascular events, especially in patients at high risk for adverse sequelae. The combination of clopidogrel plus aspirin is effective in preventing coronary stent thrombosis. Since clopidogrel is given orally, long-term use is feasible. Long-term therapy is also safe and well tolerated. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial investigators sought to determine if the benefits seen with clopidogrel in secondary prevention and in preventing stent thrombosis would be seen in the short-term and long-term treatment of patients presenting with acute coronary syndromes^1,2.

For the treatment of patients hospitalized with acute coronary syndrome without ST segment elevation:
In one CURE trial compared clopidogrel plus aspirin with placebo plus aspirin therapy in patients hospitalized within 24 hours after the onset of symptoms of acute coronary syndrome without ST segment elevation. The mean duration of treatment was 9 months. Total serious adverse events were not reported. There was no significant difference in total mortality.

Compared with placebo plus aspirin, clopidogrel plus aspirin significantly reduced the absolute risk of the first primary outcome, which was defined as the composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (9.3% vs. 11.4%, ARR =2.1%, NNT =48). About half of the total absolute risk reduction in the first primary outcome was already achieved after 1 month of therapy (4.3% vs. 5.4%, ARR =1.1%, NNT=91). The number of pills needed to prevent 1 event in the first month was 3003 (Calculated based on 91 patients needed to treat for 30 days and taking into consideration the recommended dose (300 mg = 4 pills the first day of therapy, and 75 mg = 1 pill for each day afterwards). An average of 8 more months of combined therapy with clopidogrel plus aspirin was required to achieve the additional half of the absolute risk reduction. The number of pills needed to prevent 1 event during the duration of the entire trial was 13,104 (Calculated based on 48 patients needed to treat for a mean of 9 months and taking into consideration the recommended dose (300 mg = 4 pills the first day of therapy, and 75 mg = 1 pill for each day afterwards)³.

The reduction in the first primary outcome was mainly due to a decreased rate of myocardial infarction (5.2% v. 6.7%, ARR= 1.5%, NNT= 67) which was most likely seen in patients considered to have a high risk of future cardiovascular events (ARR =4.8%, NNT =21), compared with patients with either low or intermediate risk (ARR =1.6%, NNT =63), according to a modification of the TIMI risk score. A decrease in refractory ischemia (1.4% vs. 2.0%, ARR= 0.6%, NNT= 167), and in revascularization procedures (20.8% vs. 22.7%, ARR= 1.9%, NNT= 53) also occurred during the initial hospitalization, but not during the entire trial⁴.

Adding clopidogrel to aspirin was also associated with a significantly increased incidence of bleeding episodes (8.5% vs. 5.0%, ARI= 3.5%, NNH= 29), despite exclusion of patients judged “at high risk of bleeding”. There was an increase in both, major (3.7% vs. 2.7%, ARI= 1%, NNH= 100) and minor bleeding episodes (5.1% vs. 2.4%, ARI= 2.7%, NNH= 37). Approximately half of the total excessive major bleeds in the clopidogrel plus aspirin group occurred during the first month of therapy (2.0% vs. 1.5%, ARI= 0.5%, NNH= 200)⁴.

For the treatment of patients undergoing a percutaneous coronary intervention:

Two DBRCTs (PCI-CURE study and CREDO trial) compared clopidogrel plus aspirin with placebo plus aspirin therapy in patients undergoing a percutaneous coronary intervention. The conclusions for the management of patients undergoing a percutaneous coronary intervention are confounded by the differences in the 2 available studies in terms of type of patients included, study design and definition of outcomes.

The CREDO trial included patients with a more stable, less acute baseline status than the PCI-CURE study. The PCI-CURE study included only patients hospitalized with acute coronary syndrome without ST-segment elevation who eventually underwent a percutaneous coronary intervention.

In the PCI-CURE study, when PCI was performed patients randomized to clopidogrel had received the drug for a mean of 10 days, compared with a mean of 9.8 hours for patients treated in the CREDO trial.

Routine periodic determinations of cardiac enzymes were performed in the CREDO trial, but not in the PCI-CURE study, leading to a higher detection of asymptomatic myocardial infarctions in the former trial.

Urgent target vessel revascularization was defined different in both trials.

Major bleeding episodes were defined different in both trials^5,6,7.

The PCI-CURE study:
There was no difference in mortality when clopidogrel was added to aspirin in patients undergoing a PCI. There was a decrease in cardiovascular morbidity. Treatment with clopidogrel plus aspirin was associated with a reduction in the first primary outcome, which was defined as the composite of cardiovascular death, myocardial infarction; or urgent revascularization procedures by 30 days after PCI (4.5% v. 6.4%, ARR= 1.9%, NNT= 53) which was almost entirely due to a decreased rate of myocardial infarctions by 30 days after PCI (2.1% vs. 3.8%, ARR= 1.7%, NNT= 59). Furthermore, since most patients received open-label thienopyridines after PCI for several weeks, the difference observed at 30 days after PCI was mainly due to the effects of clopidogrel treatment prior to PCI.
At the end of follow-up (mean 9 months), patients treated with clopidogrel plus aspirin had a lower incidence of myocardial infarction (8.1% vs. 11.4%, ARR= 3.3%, NNT= 30). However, almost the entire total absolute risk reduction in myocardial infarction was achieved by 1 month after PCI. The same group also had a reduction in the need for any revascularization procedure (14.2% vs. 17.1%, ARR= 2.9%, NNT= 34). There was no difference in major bleeding episodes, but patients receiving clopidogrel plus aspirin had a higher incidence of minor bleeds (3.5% vs. 2.1%, ARI= 1.4%, NNH= 71)^8,9.

The CREDO trial:
In the CREDO trial, there was no difference in mortality. Treatment with clopidogrel plus aspirin was associated with a non-significant reduction in the primary outcome, which was defined as the composite of death, myocardial infarction, or urgent target vessel revascularization at 28 days after PCI (6.8% vs. 8.3%, p=0.23). When considered separately, neither of the components of the primary outcome was significantly different between the groups.
The group assigned to clopidogrel plus aspirin had a reduction in the primary outcome at 1 year, which was defined as the composite of death, myocardial infarction, or stroke (8.5% vs. 11.5%, ARR= 3.0%, NNT= 33). However, there was no difference if each component was analyzed individually. Furthermore, the same group also had non-statistically significant excess in major bleeding episodes, which numerically counteracted the total number of myocardial infarctions or revascularization procedures prevented.^8,9

Critical appraisal of included RCTs:

Several currently recommended strategies for the treatment of acute coronary syndromes without ST-segment elevation include the use of an intravenous glycoprotein IIb/IIIa receptor antagonist for high-risk patients, or for patients in whom a PCI is planned 12-14. However, in the CURE trial only 369 patients (5.9%) in the clopidogrelgroup, and 454 patients (7.2%) in the placebo group received such treatment, even though more than 15% of the patients in each group were eventually classified as high risk 2, and around 21% of patients in each group underwent a PCI 6. This is probably because the CURE trial was performed before the routine use of GpIIb/IIIa receptor antagonist became commonplace in “high risk” patients.

The more extensive use of the combination of a glycoprotein IIb/IIIa receptor antagonist with clopidogrel plus aspirin in current clinical practice could result in different benefits and adverse outcome rates compared with the results of the CURE and CREDO trials. For example, in a retrospective study of 299 patients undergoing percutaneous coronary intervention and all treated with clopidogrel in addition to a glycoprotein (GP) IIb/IIIa receptor antagonist, the incidence of hemorrhage was 11%¹⁶. Although the severity of bleeds was not described, the incidence was considerably higher than the combined incidence of major and minor bleeding events reported in either the PCI-CURE or the CREDO trials.

For patients undergoing PCI, the study design for both available trials (PCI-CURE and CREDO) cannot answer the question of whether the long-term reduction in events achieved with clopidogrel plus aspirin therapy was due entirely to the prolonged treatment or was due at least partially to a delayed benefit derived from acute treatment. Neither of the trials re-randomized patients to clopidogrel or placebo after the open label thienopyridine/ASA treatment following PCI. This is especially important for the PCI-CURE trial, in which patients received the study drug for a mean of 10 days before the open label period: when long term treatment with either clopidogrel or placebo started after the open label period, the baseline conditions for both groups were no longer the same. This long-term benefit from an early treatment effect appears less important in the CREDO trial since patients received only 1 dose of clopidogrel before the open label period and there was no significant acute events reduction (the difference in the primary outcome at 28 days was not significant).

In the PCI-CURE study, the main benefit was a reduction in myocardial infarction. The greater reduction occurred early, during the first month of therapy. Since most patients received open-label thienopyridines after PCI for several weeks, the reduction in myocardial infarctions observed at 30 days after PCI was mainly due to the effects of clopidogrel treatment prior to PCI.

In the CREDO trial, there was a non-significant trend toward a lower incidence of myocardial infarction and urgent revascularization procedures at 28 days after PCI. It is possible that the less acute population included and the shorter duration of treatment before PCI could explain the failure to demonstrate a statistically significant short-term benefit (compared with the results in PCI-CURE). However, the more frequent use of a GpIIb/IIIa receptor antagonist in CREDO can also be involved in some of the differences.

Unstable angina, one of the most important non-ST segment elevation acute coronary syndromes, was the reason to perform a PCI in 53% of patients included in the CREDO trial. Given that combined treatment with clopidogrel and aspirin reduced the cardiovascular morbidity in patients with acute coronary syndromes without ST-segment elevation in the PCI-CURE study, it would be interesting to know the segregated results in the group of patients with more stable coronary conditions included in the CREDO trial. The benefits and risks of treatment with clopidogrel plus aspirin are unknown in patients undergoing a PCI for reasons other than acute coronary syndrome.

Incomplete reporting of total and specific serious adverse events limits understanding of the overall health impact of clopidogrel plus aspirin treatment. Clarity is also needed on the clinical significance of the outcome events. For example, although both are considered as major bleeds, there is a great difference in clinical significance between a hemorrhagic stroke and a bleed requiring transfusion but which leaves no important sequelae. The same could be true for a large myocardial infarction leading to congestive heart failure, compared with a periprocedural small asymptomatic infarction diagnosed by an increase in cardiac enzymes. This missing information is needed to define the overall benefit/harm ratio derived from the long-term use of clopidogrel in addition to aspirin^10,11,12.

CONCLUSION:
Clinical Impact

A licence submission has been made for the use of clopidogrel in addition to aspirin to reduce both early and long-term atherothrombotic events in patients with acute coronary syndrome (ACS)¹³.
This is based upon data from the CURE study (Clopidogrel in Unstable Angina to Prevent Recurrent Events) which sought to employ the additive antiplatelet effects of aspirin and clopidogrel in the treatment of ACS without ST- segment elevation. The combination was compared with aspirin alone for between 3 and 12 months (mean 9 months). The results of a subgroup analysis in patients undergoing percutaneous coronary intervention were published as the PCI-CURE study¹⁴.
In CURE, the relative risk of the primary outcome of a composite of death from cardiovascular causes, non-fatal myocardial infarction or stroke was 0.80 (95% CI 0.72 to 0.90) with the clopidogrel/aspirin combination. For this composite with refractory ischaemia, the relative risk was 0.86 (95% CI 0.79 to 0.94). The corresponding absolute risk reductions for the primary outcomes were 2.1% (NNT 48) and 2.3% (NNT 44), respectively. The study was designed to assess the composite outcomes. The results demonstrate this significance was achieved. Each individual endpoint would not be expected to achieve significance at a nominal level. However, the largest number of events was for myocardial infarction. This individual endpoint did attain statistical significance^15,16.
Maximum absolute benefit with clopidogrel appeared to occur at an early stage in treatment. Optimum duration of treatment remains to be defined and needs to balance the risks of bleeding against this evidence of early benefit¹⁷.
Major bleeding (substantially disabling bleeding, intraocular bleeding leading to loss of vision or bleeding necessitating the transfusion of at least two units of blood) was significantly more common in the clopidogrel group. The absolute risk increase was 1%, yielding a NNH of 100¹⁸.

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