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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 1  |  Issue : 1  |  Page : 35-39

Clinical outcomes of switching antiplatelet therapy from prasugrel to clopidogrel after 3–6 months of percutaneous coronary intervention with drug-eluting stents: A preliminary study


1 Department of Pharmacy Practice, Deccan School of Pharmacy, Hyderabad, India
2 Department of Cardiology, Deccan College of Medical Sciences, Hyderabad, India

Date of Web Publication24-Aug-2018

Correspondence Address:
Dr. Shaheda Siddiqui
Assistant Professor, Department of Pharmacy Practice, Deccan School of Pharmacy, Hyderabad
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IHJI.IHJI_12_17

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  Abstract 


Introduction: Dual antiplatelet therapy comprising aspirin and a P2Y12-receptor inhibitor for 1 year is the recommended treatment for the prevention of recurrent thrombotic events in patients who have undergone percutaneous coronary intervention (PCI) with the implantation of drug-eluting stent (DES). Objectives: To assess the safety and efficacy of switching the subjects from prasugrel to clopidogrel after 3–6 months of PCI with DES. Materials and methods: It is a single-center, prospective study conducted in a tertiary care hospital. The study included 100 subjects who underwent PCI with DES using prasugrel as the initial antiplatelet agent along with aspirin. Between 3 and 6 months after PCI, the patients were switched from prasugrel to clopidogrel without a loading dose. These subjects were followed up at day 28 and day 90 after switch for adverse events. Results: The mean age of subjects was 52.58±10.14 years. Of the total subjects, 59% were male and 41% were female. Approximately 53% subjects were switched after 3 months of PCI, whereas 47% were switched after 6 months. At day 28 and day 90 after switch, no major adverse cardiovascular events (including stent thrombosis) were reported. Only two episodes of minor bleeding were observed between day 28 and day 90. Conclusion: In this preliminary study, no major events, ischemic or bleeding, during the follow-up period after the subjects were switched from prasugrel to clopidogrel were reported. These findings suggest that switching the subjects from prasugrel to clopidogrel after 3–6 months of PCI may be safe and effective.

Keywords: Clopidogrel, drug-eluting stents, percutaneous coronary intervention, prasugrel, switch antiplatelet agents


How to cite this article:
Siddiqui S, Reddy GR, Sania H, Hani H, Shoukath M, Nooreen M, Unni VK, Kadloor P. Clinical outcomes of switching antiplatelet therapy from prasugrel to clopidogrel after 3–6 months of percutaneous coronary intervention with drug-eluting stents: A preliminary study. Indian Heart J Interv 2018;1:35-9

How to cite this URL:
Siddiqui S, Reddy GR, Sania H, Hani H, Shoukath M, Nooreen M, Unni VK, Kadloor P. Clinical outcomes of switching antiplatelet therapy from prasugrel to clopidogrel after 3–6 months of percutaneous coronary intervention with drug-eluting stents: A preliminary study. Indian Heart J Interv [serial online] 2018 [cited 2018 Dec 14];1:35-9. Available from: http://www.ihji.org/text.asp?2018/1/1/35/239775




  Introduction Top


Dual antiplatelet therapy (DAPT) involving aspirin and a P2Y12 inhibitor is a key aspect of the treatment for preventing the atherothrombotic events in patients with acute coronary syndrome, especially those who have undergone percutaneous coronary intervention (PCI).[1],[2]Clopidogrel is the most widely used oral P2Y12-receptor inhibitor as its safety and tolerability is well established. Nevertheless, substantial proportion of patients have recurrent cardiovascular events including stent thrombosis.[3]

In recent years, newer generation P2Y12-receptor inhibitors—prasugrel, ticagrelor, and cangrelor—have become available for clinical use. These agents are characterized by a potent, rapid action with predictable and steady antithrombotic effects that significantly reduce thrombotic and ischemic events compared to clopidogrel.[4],[5]Though pretreatment with clopidogrel in the patients undergoing PCI has been the standard treatment in various health centers in the past decade, the use of newer adenosine diphosphate–receptor inhibitors as the initial antiplatelet therapy is an emerging trend.[6]

However, the use of newer P2Y12-receptor inhibitors can be limited by the higher risk of bleeding and cost compared to clopidogrel.[7] These factors can call for the switching of the patients from more potent thienopyridine to clopidogrel. However, the strategy of switching the patients from newer generation thienopyridine to clopidogrel is a conundrum for many clinicians. In spite of being widely practiced, the data available on switching of antiplatelet agents are inadequate.

Limited studies are available that have put to test the strategy of switching the patients from more potent prasugrel to lesser potent clopidogrel, especially in the routine clinical scenario. Thus, this study was conducted in a tertiary care hospital, Princess Esra Hospital and Deccan College of Medical Sciences (DCMS) at Hyderabad, Telangana, India.


  Objectives Top


To assess the safety and effectiveness of switching the subjects from prasugrel to clopidogrel after 3–6 months of PCI with drug-eluting stents.


  Design and Settings Top


It is a single-center, observational, noninterventional, prospective study, which was carried out in a tertiary care hospital of Hyderabad, Princess Esra Hospital and DCMS, for 6 months, that is, from October 1, 2016 to March 31, 2017. A total of 100 subjects who underwent PCI for acute coronary syndrome and received 10mg once daily maintenance dose of prasugrel for 3–6 months were included after they were explained about the objectives of the study. A written informed consent was obtained from all the subjects. The study was initiated only after the approval of the institutional ethics committee.

Inclusion criteria

  1. Age between 18 and 75 years


  2. Received prasugrel shortly before PCI


  3. Switched to clopidogrel 3–6 months after PCI


  4. Patients receiving DAPT


  5. Patients willing to give consent


Exclusion criteria

  1. Conditions where antiplatelets are contraindicated
    • • Pregnant women


    • • Thrombocytopenia


  2. Conditions where risk of bleeding with prasugrel is high
    • • Age below 18 years


    • • Patients >75 years of age


    • • Patients weighing <60 kg


    • • History of old cardiovascular accident


  3. Other conditions
    • • Patients not willing to give consent


    • • Hypersensitivity to the drugs or any of its recipients



  Materials and Methods Top


Protocol

On the basis of selection criteria, subjects were identified in the outpatient department of cardiology. History was obtained from the patients with reference to the duration for which they took prasugrel after undergoing PCI with special reference to the history of bleeding, major adverse cardiovascular events (MACE), or ischemic incidence. A switch from prasugrel to clopidogrel was carried out mainly because of financial constraints.

A minimum interval of 12h was maintained between the first dose of clopidogrel (75mg) and the last dose of prasugrel (10mg). Loading dose of clopidogrel was not given. The patients were then followed up at day 28 and day 90 after switch. Aspirin was continued at a dose of 150mg once daily.

Analysis of outcomes

The study end points included the rate of all-cause death, myocardial infarction (MI), stroke, or stent thrombosis; the rate of major and minor bleeding using the thrombolysis in myocardial infarction (TIMI) definition at day 28 and day 90 after switch.[8]

Statistical analysis

The study data were analyzed in terms of descriptive and inferential analysis. The continuous variables were presented as mean ± standard deviation (SD) and the categorical variables as numbers. Statistical analysis was carried out using GraphPad Software Version 7.03 (San Diego, USA).


  Results Top


Clinical characteristics

The mean age of the study population was 53.33±9.986 years (mean ± SD). Majority of the study subjects were of the age group 41–50 years (37%). The sex ratio of the study subjects was 59:41 (male/female). The clinical characteristics of the subjects are summarized in [Table 1].
Table 1: Clinical characteristics of the subjects

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Indications for percutaneous coronary intervention

In this study, the major indication for PCI was MI (82%) of which ST-elevated myocardial infarction (STEMI) was 61% and non-ST-elevated myocardial infarction (NSTEMI) was 21%, unstable angina (10%), and chronic stable angina (2%) [Figure 1].
Figure 1: Indications for percutaneous coronary intervention among the study subjects

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Medications

The medications received by the study subjects are mentioned in [Figure 2].
Figure 2: Different drugs received by the study subjects. ACE = angiotensin converting enzyme

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Clinical outcomes

After the subjects were switched from prasugrel to clopidogrel, no ischemic events (angina, MI, or stent thrombosis) were observed on follow-up at day 28 and day 90.

Only two minor bleeding events were reported within 90 days after switch (none within 28 days) [Figure 3].
Figure 3: Bleeding events observed in the study subjects

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  Discussion Top


In a routine clinical practice, switching between the P2Y12 inhibitors is a familiar scenario. Though the safety and tolerability of clopidogrel is well established, studies have raised concerns regarding the variable response of clopidogrel. Among the nonresponders, it elevates the risk of ischemic events and on the other hand, among the hyperresponders, it has the potential to increase the risk of bleeding.[9],[10]

Prasugrel is a prodrug that is converted to its active metabolite, which irreversibly binds to the P2Y12 receptors.[11] The lesser subsequent metabolism of prasugrel leads to its higher concentration. Thus, it is more potent than clopidogrel.[1] Prasugrel has a predictable pharmacokinetic profile, rapid platelet inhibition, and minor interindividual variability.[7],[12],[13]Therefore, it is preferable when the risk of thrombosis is the highest, that is, in the initial few months after PCI.

In this study, the loading dose of clopidogrel was not given at the time of switch as both prasugrel and clopidogrel act on the same platelet receptor–binding site; therefore, switching to maintenance dose of clopidogrel does not necessitate the administration of a loading dose,[14] and the risk of stent thrombosis after 3–6 months of PCI is very less when compared to the initial few months. Even in the TOPIC trial (timing of platelet inhibition after acute coronary syndrome), where the switch was carried out only after 1 month of PCI, no loading dose was given. It was found that giving a loading dose of clopidogrel 3–6 months after PCI may unnecessarily increase the bleeding risk without substantial additional benefits. No current consensus on giving loading dose during switch was obtained.

The TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38) trial has reported the superiority of prasugrel in 13,608 patients undergoing PCI.[7] Major bleeding increased (2.4% vs. 1.8%; hazard ratio, 1.32; P = 0.03) along with the life-threatening, nonfatal, and fatal bleeding in the prasugrel group. Most of the net clinical benefits were observed in the initial 5 days, whereas the major bleeding increased after the initial 30 days of the procedure.[15] These results raise the question on the safety of long-term treatment with prasugrel, thus suggesting a possible role for switch to clopidogrel when the higher risk period of ischemic events or MACE including stent thrombosis subsides.

The TOPIC trial has concluded that in patients on aspirin plus ticagrelor or prasugrel without any evidence of an adverse event in the first month after PCI, switching DAPT strategy to aspirin plus clopidogrel may reduce the risk of bleeding recurrence without an increased risk of ischemic events.[14]

The timing of switch to clopidogrel is 3–6 months in our study, whereas it was only 1 month in TOPIC trial. The results of both the studies suggest that such a strategy is safe and effective. The two cases of minor bleeding observed among the study subjects were after the initial 28 days of the switching to clopidogrel. It is noteworthy that no major events, neither cardiac nor bleeding, were reported within 28 days.

The results of our study diverge from that of the study by Kerneis et al.,[16] in which a switch from prasugrel to clopidogrel in 31 patients with acute coronary syndromes concluded that such a strategy might unmask the group of nonresponders to clopidogrel with unknown clinical outcomes.

Limitations of the Study

The smaller study sample may preclude detecting a rare event such as late stent thrombosis. As this is not a randomized-controlled trial, the presence of confounding factors may affect the study results. However, the larger randomized-controlled trial, the TOPIC trial, has confirmed the findings of our study.


  Conclusion Top


As there were no major adverse events, ischemic or bleeding, switching the antiplatelet regimen of the patients from prasugrel to clopidogrel after 3–6 months of PCI is probably safe and effective. The data reported suggest the advantageous use of higher potent prasugrel during the very high-risk period after PCI and shifting to safer clopidogrel during the low-risk period. However, these findings need to be confirmed in a larger, adequately powered, randomized study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Brandt JT, Payne CD, Wiviott SD, Weerakkody G, Farid NA, Small DS, et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: Magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 2007;1:66.e9-16.  Back to cited text no. 1
    
2.
Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, et al.; ESC Scientific Document Group. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;1:267-315.  Back to cited text no. 2
    
3.
Aradi D, Kirtane A, Bonello L, Gurbel PA, Tantry US, Huber K, et al. Bleeding and stent thrombosis on P2Y12-inhibitors: Collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention. Eur Heart J 2015;1:1762-71.  Back to cited text no. 3
    
4.
Gurbel PA, Erlinge D, Ohman EM, Neely B, Neely M, Goodman SG, et al.; TRILOGY ACS Platelet Function Substudy Investigators. Platelet function during extended prasugrel and clopidogrel therapy for patients with ACS treated without revascularization: The TRILOGY ACS platelet function substudy. JAMA 2012;1:1785-94.  Back to cited text no. 4
    
5.
Wiviott SD, Trenk D, Frelinger AL, O’Donoghue M, Neumann FJ, Michelson AD, et al.; PRINCIPLE-TIMI 44 Investigators. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: The prasugrel in comparison to clopidogrel for inhibition of platelet activation and aggregation-thrombolysis in myocardial infarction 44 trial. Circulation 2007;1:2923-32.  Back to cited text no. 5
    
6.
Larmore C, Effron MB, Molife C, DeKoven M, Zhu Y, Lu J, et al. “Real-world” comparison of prasugrel with ticagrelor in patients with acute coronary syndrome treated with percutaneous coronary intervention in the United States. Catheter Cardiovasc Interv 2016;1:535-44.  Back to cited text no. 6
    
7.
Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al.; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;1:2001-15.  Back to cited text no. 7
    
8.
Antman EM, Cohen M, Bernink PJ, McCabe CH, Horacek T, Papuchis G, et al. The TIMI risk score for unstable angina/non-st elevation MI: A method for prognostication and therapeutic decision making. JAMA 2000;1:835-42.  Back to cited text no. 8
    
9.
Feher G, Feher A, Pusch G, Koltai K, Tibold A, Gasztonyi B, et al. Clinical importance of aspirin and clopidogrel resistance. World J Cardiol 2010;1:171-86.  Back to cited text no. 9
    
10.
Gurbel PA, Bliden KP, Samara W, Yoho JA, Hayes K, Fissha MZ, et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: Results of the CREST study. J Am Coll Cardiol 2005;1:1827-32.  Back to cited text no. 10
    
11.
Sabatine MS, Cannon CP, Gibson CM, López-Sendón JL, Montalescot G, Theroux P, et al.; CLARITY-TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;1:1179-89.  Back to cited text no. 11
    
12.
Angiolillo DJ, Badimon JJ, Saucedo JF, Frelinger AL, Michelson AD, Jakubowski JA, et al. A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: Results of the optimizing anti-platelet therapy in diabetes mellitus (OPTIMUS)-3 trial. Eur Heart J 2011;1:838-46.  Back to cited text no. 12
    
13.
Sibbing D, Aradi D, Jacobshagen C, Gross L, Trenk D, Geisler T, et al.; TROPICAL-ACS Investigators. A randomised trial on platelet function-guided de-escalation of antiplatelet treatment in ACS patients undergoing PCI. Rationale and design of the testing responsiveness to platelet inhibition on chronic antiplatelet treatment for acute coronary syndromes (TROPICAL-ACS) trial. Thromb Haemost 2017;1:188-95.  Back to cited text no. 13
    
14.
Cuisset T, Deharo P, Quilici J, Johnson TW, Deffarges S, Bassez C, et al. Benefit of switching dual antiplatelet therapy after acute coronary syndrome: The TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study. Eur Heart J 2017;1:3070-8.  Back to cited text no. 14
    
15.
Kaul S, Shah PK, Diamond GA. Abstract 4014. Timing of benefit with prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: Reanalysis of TRITON-TIMI 38 results. Circulation 2008;1:S818-9.  Back to cited text no. 15
    
16.
Kerneis M, Silvain J, Abtan J, Cayla G, O’Connor SA, Barthélémy O, et al. Switching acute coronary syndrome patients from prasugrel to clopidogrel. JACC Cardiovasc Interv 2013;1: 158-65.  Back to cited text no. 16
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1]



 

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