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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 6  |  Issue : 3  |  Page : 97-101

A comparative study of tirofiban plus enoxaparin versus enoxaparin alone along with dual antiplatelet blockade in the management of patients with non-ST elevation acute coronary syndrome


1 Department of Cardiology, King George's Medical University, Lucknow, Uttar Pradesh, India
2 Department of Cardiology, Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Web Publication12-Sep-2018

Correspondence Address:
Dr. Akshyaya Pradhan
Department of Cardiology, King Georges Medical University, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/heartindia.heartindia_32_18

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  Abstract 


Introduction: Antithrombotic therapy in patients with non-ST elevation acute coronary syndrome (NSTE-ACS) includes dual antiplatelet therapy (DAPT) along with enoxaparin. However, resistance to antiplatelet action of aspirin and clopidogrel is well known and is about 27% (0-57%) and 30%, respectively. Hence the use of GPIIb/IIIa inhibitor appears to be a reasonable option as they act on the final common pathway of platelet aggregation. Though frequently used in patients undergoing percutaneous intervention (PC1), their use in patients not undergoing such procedure is not popular despite evidence in literature.
Materials and Methods: This study was done on 44 patients of NSTE-ACS managed conservatively. The patients were randomized in a 1:1 fashion in two groups. The patients in group 1 received tirofiban(0.4μg/kg/min i.v for 30 min followed by 0.1μg/kg/min for 48 hours) in addition to aspirin (325 mg stat followed by 75 mg P.O. daily), clopidogrel (300 mg stat followed by 75 mg P.O. daily) and enoxaparin (1 mg/kg S.C bid for 5 days). The group 2 patients received DAPT and enoxaparin only, in similar doses. Both the groups received antianginal therapy as appropriate and statins.
Results: The study showed the benefits of adding tirofiban to enoxaparin and DAPT irrespective of age, sex, presence or absence of diabetes and dyslipidemia, ECG changes, troponin positivity and TIMI score in patients with NSTE-ACS. There was a significant reduction {Risk reduction (RR) of 45.4% P <0.01} in composite of primary end points refractory ischemia myocardial infarction (MI) and death with Tirofiban. No major or minor bleeding episodes were seen in any patients.
Conclusion: Thus, we conclude that tirofiban in addition to DAPT and enoxaparin reduces the risk of refractory ischemia, MI and death in patients with NSTE-ACS without any additional risk of major or minor bleeding. Therefore, we advocate this regimen in patients with NSTE-ACS managed conservatively. Large randomized study is needed to recommend this regimen.

Keywords: Antiplatelet resistance, GPIIb/IIIa inhibitors, myocardial infarction, non-ST elevation NSTE-ACS


How to cite this article:
Bhandari M, Vishwakarma P, Misra M, Narain VS, Pradhan A, Sethi R. A comparative study of tirofiban plus enoxaparin versus enoxaparin alone along with dual antiplatelet blockade in the management of patients with non-ST elevation acute coronary syndrome. Heart India 2018;6:97-101

How to cite this URL:
Bhandari M, Vishwakarma P, Misra M, Narain VS, Pradhan A, Sethi R. A comparative study of tirofiban plus enoxaparin versus enoxaparin alone along with dual antiplatelet blockade in the management of patients with non-ST elevation acute coronary syndrome. Heart India [serial online] 2018 [cited 2018 Sep 23];6:97-101. Available from: http://www.heartindia.net/text.asp?2018/6/3/97/241071




  Introduction Top


Coronary artery disease (CAD) is a major public health problem worldwide including India. Despite major advances in prevention and treatment, it remains a leading cause of death worldwide contributing to 15% of all-cause mortality.[1]

An important subgroup of CAD presents as non-ST elevation-acute coronary syndrome (NSTE-ACS). Since the most common cause is a nonocclusive thrombus on a disrupted atherosclerotic plaque, interventions acting on platelets and the coagulation cascade have become the mainstay of therapy.

The standard treatment today for these patients comprises of dual antiplatelet blockade (Aspirin+Clopidogrel), Enoxaparin, PCI/CABG surgery [I-A indication][2]

Today, most of these patients are managed by an early invasive strategy. However, facilities for coronary intervention are not widely available in our country; therefore, a majority of these patients has to be managed conservatively using enoxaparin and dual antiplatelet blockade. However, resistance to the action of aspirin and clopidogrel is a well-known fact (0%–57% and 30%, respectively).[3],[4],[5],[6] There are no readily available laboratory parameters to measure resistance to the antiplatelet action of clopidogrel, and the direct methods to assess its antiplatelet action (aggregometry) are too cumbersome to be used practically. Thus, resistance is judged clinically and the occurrence of an adverse event may be the first clue to its presence. To overcome this shortcoming, addition of GPIIb/IIIa inhibitors which act on the final common pathway of platelet activation is likely to be effective in such a situation. GPIIb/IIIa inhibitors are recommended as an adjunctive therapy in patients undergoing PCI. They prevent post-PCI thrombotic complications. This may be because GpIIb/IIIa inhibitors are beneficial to overcome the resistance of aspirin and clopidogrel. Tirofiban, a GPIIb/IIIa inhibitor, has been found to reduce the incidence of refractory ischemia, myocardial infarction (MI), and death in patients with NSTE-ACS managed conservatively (PRISM and PRISM-PLUS Trial).[7],[8] It is recommended by ACC and ESC guidelines (Class IIa-A indication) in patients with NSTE-ACS managed conservatively.[2] It is a potent antiplatelet agent which is easily available, less expensive, and may be beneficial as an additive drug in patients managed noninvasively. However, it is not used routinely in patients with NSTE-ACS not undergoing PCI.


  Materials and Methods Top


The study comprised of 44 patients of NSTE-ACS (28 males and 16 females). The mean age was 58.9 ± 7.86 years. The diagnosis of NSTE-ACS was made by history, electrocardiographic (ECG) examination, and estimation of cardiac biomarkers (troponin-I/CKMB enzyme). Patients with significant renal or hepatic dysfunction, comorbidities, pregnant females with NSTE-ACS, and patients with electrical or hemodynamic instability were excluded from the study. The patients were divided in a 1:1 randomized fashion into two groups.

  • Group 1 (tirofiban group): In this group, patients received enoxaparin and tirofiban along with dual antiplatelet therapy (DAPT)
  • Group 2 (control group): In this group, patients received enoxaparin and DAPT.


The patients in both the groups received other ancillary treatment (statins, β-blockers, etc.). The dose of enoxaparin was 1 mg/kg SC bid for 5 days and that of tirofiban was 0.4 μg/kg/min intravenously for 30 min followed by maintenance dose of 0.1 μg/kg/min for 48 h. The loading dose of aspirin was 325 mg followed by 75 mg PO daily and that of clopidogrel was 300 mg followed by 75 mg PO daily. The patients were followed on days 3, 7, 30, and 6 months for the occurrence of primary end points in the form of refractory ischemia, MI, and death and a composite of them.


  Results Top


Demographic characteristics

The total number of patients included in our study was 44. Among them, 28 (63.6%) were males and 16 (36.4%) were females. Nearly 43.2% of the patients (19 out of 44) were ≥65 years of age. The mean age in males and females was 59.6 ± 9.44 and 56.3 ± 9.27 years, respectively. The overall mean age was 58.9 ± 7.86 years and the male-to-female ratio was 3.5:2 [Table 1](a)].
Table 1: (a) Age and sex distribution, (b) Patient characteristics



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In tirofiban group, 36.4% of the patients (8 out of 22) were hypertensive compared with 31.8% (7 out of 22) in the control group. The difference in the prevalence of hypertension in the two groups was insignificant (Z = 0.318, P > 0.05). In the tirofiban group, 27.3% of the patients (6 out of 22) were diabetic compared with 13.6% of patients (3 out of 22) in the control group. The difference in the prevalence of diabetes in the two groups was insignificant (Z = 1.121, P > 0.05). Smoking history was present in four patients in the tirofiban group and six patients in the control group. Troponin I was elevated in 63.6% of the patients (14 out of 22) in the tirofiban group compared with 50% of the patients (11 out of 22) in the control group. The difference in the status of troponin I in the two groups was insignificant (P > 0.05). In the present study, ECG was abnormal in all the patients. In the tirofiban group, five patients (22.7%) had T-wave inversion and the rest (77.3%) had ST depression. In the control group, T-wave inversion and ST depression were present in 11 patients (50% each). Congestive heart failure was present in three patients in the tirofiban group and two patients in the control group group [Table 1](b)].

Primary and composite end points

The incidence of refractory ischemia as judged by recurring chest pain despite treatment was 40.9% in the control group as compared with 13.6% in the tirofiban group. There was a risk reduction of 27.3% in the favor of tirofiban which was significant (Z = 2.158, P < 0.01). MI occurred in 13.6% of patients in the control group as compared with 4.5% in the tirofiban group, with a risk reduction of 9.1% (Z = 1.04, P > 0.05). The incidence of death was 9.1% in the control group, while none of the patients died in the tirofiban group. There was overall overall 45.4% reduction in composite of all primary endpoints in the group receiving tirofiban, which was highly significant (Z = 3.06, P < 0.01) [Table 2] and [Figure 1].
Table 2: Primary and composite end points

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Figure 1: Difference in primary and composite end points in the two groups

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Subgroup analysis

The incidence of primary end points was reduced by 4.5% in diabetic patients by addition of tirofiban (Z = 1.44, P > 0.05). The incidence was reduced by 27.3% in patients with dynamic ECG changes (ST depression). The percentage of troponin I patients who developed primary end points was 14.3% in the tirofiban group compared with 63.6% in the control group, causing a risk reduction of 49.3% which was significant (Z = 2.158, P < 0.01). The incidence of end points was reduced by 18.2% by tirofiban in patients with high Thrombolysis in Myocardial Infarction (TIMI) score (≥3) (Z = 1.022, P > 0.05) [Figure 2].
Figure 2: Incidence of end points in various subgroups

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  Discussion Top


NSTE-ACS remains one of the leading causes of death worldwide despite major advances. These patients need an early invasive strategy, either PCI or CABG surgery. However, a large majority of these patients are managed conservatively in our country using enoxaparin, aspirin, and clopidogrel along with β-blockers and statins. Adding clopidogrel to aspirin increases antiplatelet response by 20% over that of aspirin alone which contributes to 50% of antiplatelet action. However, despite DAPT, the patients with NSTE-ACS develop recurrent ischemic events and/or may die in some cases. In the CURE trial, 9.3% of patients still had recurrent ischemia, MI, or death on DAPT compared with 11.4% on aspirin alone.[9] This may be due to resistance to the antiplatelet action of these drugs. The addition of tirofiban to this treatment regimen may benefit these patients. In the present study, we found the benefits of adding tirofiban in NSTE-ACS patients. The incidence of end points was reduced by 18.2% in the tirofiban group which is in accordance to PRISM-PLUS study where the incidence of end points was reduced by 32%.[8] Similarly, tirofiban reduced the incidence of primary end points in various subgroups. In accordance to the results of a previous study done by Roffi et al.,[10] where the event rate was reduced from 6.2% to 4.0% (P > 0.004), the present study also showed the reduction of 4.5% in event rate in the tirofiban group (P > 0.05). There was a significant reduction of 49.3% in the event rate in patients having positive troponin I. Similar benefits were seen in a study done by Heeschan et al.,[11] who studied the effects of tirofiban in patients of NSTE-ACS with positive troponin I. According to a study done by Marrow et al. (2001),[12] tirofiban showed its beneficial effects in reducing the events in patients with high TIMI score in this study.

Thus, in our study there was a significant reduction in the incidence of refractory ischemia (RR 27.3%) and composite of all end points (RR 45.4%). The incidence of MI and death was also reduced (RR 9.1% each) although not significantly. The benefits of tirofiban were specifically seen in high-risk patients, that is, patients with diabetes, ST depression, high TIMI score, and positive troponin I as observed in the subgroup analysis. The incidence of events was statistically significantly reduced in patients having ST depression and positive troponin I patients. No major or minor bleeding episodes were seen in any patients. However, there was limitation of cohort being small, making subgroup analysis inappropriate. Thus, we recommend this study to be done on a large cohort so that appropriate results of using tirofiban in these patients can be seen.


  Conclusions Top


The standard of care today for patients with ACS is PCI/CABG surgery (ACC and ESC guidelines Class I indication, Level of evidence A).[2] Drug treatment consisting of dual antiplatelet blockade and enoxaparin along with β-blockers and statins also enjoy the similar status. At the same time, resistance to the antiplatelet actions of aspirin and clopidogrel is well known, for which easy markers are not available and occurrence of an event may be the first clue. Addition of GPIIb/IIIa inhibitors may be a step that could overcome the problem of resistance to antiplatelet drugs. However, despite a IIa-A indication,[2] their use in patients with ACS managed conservatively has not gained popularity, although they are used commonly in patients undergoing PCI procedure.

The present study comprised of 44 patients (28 males and 16 females) randomized in a 1:1 fashion into two groups. Tirofiban reduced the incidence of refractory ischemia by 27.3% (P < 0.01), MI by 9.1% (P > 0.05), and death by 9.1% (P > 0.05). The incidence of composite of all the primary end points was reduced by 45.4% (P > 0.05). Thus, refractory ischemia and composite of all primary end points were significantly reduced in the tirofiban group. Tirofiban decreased the incidence of primary end points by 4.5% in diabetic patients (P > 0.05), by 49.3% in troponin I-positive patients (P < 0.01), by 27.3% in patients with ST depression, and by 18.2% each in hypertensives, patients with T-wave inversion, and in those with high TIMI score (≥3) (P > 0.05). All the subsets of patients were benefited by tirofiban, but significance was noted in patients with ST depression and positive troponin I. The drug was well tolerated by all the patients without any adverse effects, including bleeding.

Thus, from the present study, we conclude that addition of tirofiban to enoxaparin and dual antiplatelet blockade reduces the risk of refractory ischemia, MI, and death in patients with ACS without any additional risk of major or minor bleeding. The benefits are specifically seen in high-risk patients such as those having diabetes, ST depression, positive troponin I, and high TIMI score. Therefore, we recommend the use of tirofiban as an adjunctive therapy even in patients who are managed conservatively.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Thom T, Haase N, Rosamond W, Howard VJ, Rumsfeld J, Manolio T, et al. Heart disease and stroke statistics–2006 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2006;113:e85-151.  Back to cited text no. 1
    
2.
Amsterdam EA, Wegener NK, Brindis RG, Casey Jr DE, Ganiats TG, Holmes Jr DR, et al. 2014 AHA/ACC Guidelines for the Management of the Patients with Non- ST Elevation Acute Coronary Syndromes, J of Am Coll Cardiol 2014. doi:10.1016/j.jacc 2014.09.017.  Back to cited text no. 2
    
3.
Hovens MM, Snoep JD, Eikenboom JC, van der Bom JG, Mertens BJ, Huisman MV, et al. Prevalence of persistent platelet reactivity despite use of aspirin: A systematic review. Am Heart J 2007;153:175-81.  Back to cited text no. 3
    
4.
Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramírez C, Barrera-Ramirez C, Sabaté M, et al. Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting. Thromb Res 2005;115:101-8.  Back to cited text no. 4
    
5.
Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: A review of the evidence. J Am Coll Cardiol 2005;45:1157-64.  Back to cited text no. 5
    
6.
Aleil B, Ravanat C, Cazenave JP, Rochoux G, Heitz A, Gachet C, et al. Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases. J Thromb Haemost 2005;3:85-92.  Back to cited text no. 6
    
7.
Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med 1998;338:1498-505.  Back to cited text no. 7
    
8.
Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998;338:1488-97.  Back to cited text no. 8
    
9.
Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.  Back to cited text no. 9
    
10.
Roffi M, Chew DP, Mukherjee D, Bhatt DL, White JA, Heeschen C, et al. Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients with non-ST-segment-elevation acute coronary syndromes. Circulation 2001;104:2767-71.  Back to cited text no. 10
    
11.
Heeschen C, Hamm CW, Goldmann B, Deu A, Langenbrink L, White HD, et al. Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban. PRISM study investigators. Platelet receptor inhibition in ischemic syndrome management. Lancet 1999;354:1757-62.  Back to cited text no. 11
    
12.
Morrow DA, Antman EM, Snapinn SM, McCabe CH, Theroux P, Braunwald E, et al. An integrated clinical approach to predicting the benefit of tirofiban in non-ST elevation acute coronary syndromes. Application of the TIMI risk score for UA/NSTEMI in PRISM-PLUS. Eur Heart J 2002;23:223-9.  Back to cited text no. 12
    


    Figures

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    Tables

  [Table 1], [Table 2]



 

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