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ORIGINAL ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 5  |  Page : 25-30

Outcomes with aspirin and clopidogrel versus aspirin and rivaroxaban in infrainguinal endovascular revascularization for critical limb ischemia


Department of Peripheral Vascular and Endovascular Surgery, Jain Institute of Vascular Sciences, A Unit of Bhagwan Mahaveer Jain Hospital, Bengaluru, Karnataka, India

Date of Submission06-Nov-2020
Date of Acceptance07-Dec-2020
Date of Web Publication30-Aug-2021

Correspondence Address:
B Nishan
Department of Peripheral Vascular and Endovascular Surgery, Jain Institute of Vascular Sciences, A Unit of Bhagwan Mahaveer Jain Hospital, Bengaluru
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijves.ijves_149_20

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  Abstract 


Background: The purpose of the study was to assess the benefits of dual antithrombotic therapy in the management of peripheral arterial disease in Indian population. Methods: We conducted a prospective review of patients on dual antithrombotic therapy who underwent infra-inguinal endovascular revascularisation at JIVAS for 18 months. Objectives: To study the outcomes with aspirin + clopidogrel (CA) versus aspirin + rivaroxaban (RA) after infrainguinal endovascular revascularization for critical limb ischemia. The main objective was to assess primary patency of vessel after endovascular revascularization. The secondary objectives were to study limb salvage, major adverse limb events (MALEs), major adverse cardiac events (MACEs), bleeding events (major and minor), and wound healing. Results: In the present study, a total of 104 patients underwent infrainguinal revascularization and fulfilled the inclusion criteria, of which 48 received RA and 56 received CA. The mean age was 49.8 years with no significant differences in the baseline demographics and comorbidities between the two groups. The primary objective of vessel patency was assessed measuring the ankle brachial index which was 0.91 in the RA group and 0.96 in the CA group and remained the same on follow-up till 6 months and mean trans cutaneous oxygen pressure of around 34 in both the groups. There was no significant difference in the incidence of MALE (2.1% in RA vs. 7.1% in CA; P = 0.2), MACE (6.3% in RA vs. 10.7% in CA; P = 0.4), wound healing (81% RA vs. 75% CA; P = 0.4), safety parameter of bleeding (6.3% RA vs. 3.6% CA), creatinine, and liver function tests (LFT) during the study period. Conclusion: Both the antithrombotic regimens can be considered safe and efficacious in the postoperative management of patients undergoing infrainguinal revascularization; with maintenance of primary patency, comparable wound healing, incidence of MALE and MACE, and safe with no bleeding; and no impairment in the serum creatinine and LFTs during follow-up.

Keywords: Antithrombotics, peripheral arterial disease, rivaroxaban


How to cite this article:
Nishan B, Hudgi V, Siva Krishna K, Ahsan V P, Rodney R, Raj K B. Outcomes with aspirin and clopidogrel versus aspirin and rivaroxaban in infrainguinal endovascular revascularization for critical limb ischemia. Indian J Vasc Endovasc Surg 2021;8, Suppl S1:25-30

How to cite this URL:
Nishan B, Hudgi V, Siva Krishna K, Ahsan V P, Rodney R, Raj K B. Outcomes with aspirin and clopidogrel versus aspirin and rivaroxaban in infrainguinal endovascular revascularization for critical limb ischemia. Indian J Vasc Endovasc Surg [serial online] 2021 [cited 2021 Dec 1];8, Suppl S1:25-30. Available from: https://www.indjvascsurg.org/text.asp?2021/8/5/25/324935




  Introduction Top


Critical limb ischemia (CLI) is the most severe form of lower-extremity peripheral artery disease (PAD). It is defined as lower-extremity pain that occurs at rest or in the presence of ulcers or gangrene, secondary to severe compromise of blood flow.[1]

Current guidelines recommend antiplatelet therapy, either ecosprin or clopidogrel monotherapy, for cardiovascular risk reduction in stable PAD.[2] Therefore, studies in dedicated PAD populations, with a full spectrum of relevant PAD end points, are needed to identify optimal strategies for decreasing postrevascularization ischemic risk.[3]

Dual-antiplatelet therapy (DAPT) following postendovascular revascularization has been proven beneficial. The intent of this study was to compare benefits of anticoagulation in comparison to standard DAPT in patients who underwent infrainguinal endovascular revascularization.


  Methods Top


This was a single-center, prospective, nonrandomized, observational, double-arm, comparative study done at Jain Institute of Vascular Sciences, Bhagwan Mahaveer Jain Hospital, Bangalore, including patient recruitment for a period of 1 year with follow-up at 1st, 3rd, and 6th month. The study included patients between the age group of 18 and 80 years, patients with CLI Rutherford Category 4–6, and patients who underwent infrainguinal endovascular revascularization. Patients requiring anticoagulation for any other reason and/or those with previous history of vascular intervention both surgical and endovascular or any contraindication to the use of rivaroxaban, clopidogrel, and aspirin were excluded from the study. Patients were randomly assigned to receive either rivaroxaban with aspirin (RA) or clopidogrel with aspirin (CA) following successful endovascular revascularization. All the patients were to receive aspirin at the dose of 150 mg OD and either rivaroxaban 10 mg OD or clopidogrel 75 mg OD for duration of 3 months. The primary end point was the primary patency of vessel following endovascular revascularization, and the secondary end points included limb salvage, major adverse cardiac events (MACE), major adverse limb events (MALE), wound healing, and safety outcome of bleeding both major and minor. The patient demographics routine baseline investigation, ABI, TcPO2, arterial duplex scan of index limb, and magnetic resonance/computed tomography angiography were to be recorded. The procedure performed angioplasty with or without stenting was noted. Postoperatively, the physical examination, ABI, and TcPO2 were measured to assess primary patency of vessel, wound healing, incidence of MALE and MACE, safety parameters of bleeding, hemoglobin levels, serum creatinine, and liver function test (LFT) on follow-up at 1st, 3rd, and 6th month. Descriptive statistics, Chi-square/Fisher's exact test, Student's t-test, and one-way analysis of variance were applied where appropriate.


  Results Top


The efficacy and safety were assessed in 104 patients who underwent infrainguinal revascularization procedure fulfilling the inclusion criteria, of which 48 patients received RA and 56 patients received CA.

There were no significant differences in the comorbidities at baseline between the two groups [Table 1].
Table 1: Baseline comorbidities

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There was no significant difference between the two groups with regard to the WIFI classification of wound on the index limb [Table 2].
Table 2: Wound classification

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There was a significant difference in the number of patients who underwent popliteal vessel angioplasty in the RA group as compared to CA group, while other vessel angioplasty and stenting were comparable across the two groups with no significant difference [Table 3].
Table 3: Vessel angioplasty (and stenting) of infrainguinal vessels

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The post-operative ABI improved in both the groups in comparison with preoperative ABI indicating successful revascularisation following endovascular procedure. No significant difference or drop in the ABI within the same groups on follow-up after starting antithrombotic therapy indicating maintained patency of the revascularised segment [Table 4].
Table 4: ABI

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Although a significant difference in TcPO2 exists in the pre-OP values between the two groups and on comparison to the post-OP values, there is no significant difference in the TcPO2 on follow-up within the same group which indicates the patency of the vessel.

There is no significant difference between the dependent TcPO2 comparing the post-OP values to 1st, 3rd, and 6th month which signifies patency of angioplasty vessel [Table 5] and [Table 6].
Table 5: Supine TcPO2

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Table 6: Dependent TcPO2

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There is no significant difference in the patients who underwent amputations in the two groups [Table 7].
Table 7: Major adverse limb events

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The MACE in the study population was myocardial infarction, and there was no significant difference among the two groups on follow-up at 1st, 3rd, and 6th month [Table 8].
Table 8: Major adverse cardiac events

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Although there is a significant difference in hemoglobin before surgery, there was no significant difference between the two groups on follow-up at 1st and 3rd month. No significant drop in Hemoglobin levels in both groups in preoperative, post operative and follow up periods indicating no significant risk of bleeding with antithrombotic therapy [Table 9].
Table 9: Hemoglobin

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  Discussion Top


In the present study, there was significant difference in ABI and TcPO2 in the immediate post-OP period between the two groups; however, no significant difference or worsening was observed in ABI and TcPO2 within the same group on follow-up of up to 6 months, indicating maintenance of primary patency. There was no significant difference in the incidence of MALE and MACE between the two group and can safely infer the efficacy of dual antithrombotics in preventing these occurrences. The wound healing was comparable between the two groups and no significant difference. There was no patient who suffered from major bleeding, while a few patients had minor bleeding, which was self-limiting and no significant difference between the two groups. The hemoglobin levels measured throughout the follow-up was consistent, and there was no drop in levels indicating no internal blood loss. Hence, the antithrombotics could be used safely with no major concerns in terms of bleeding. There was no significant difference between the two groups in the investigation panel for serum creatinine and LFTs, and hence, the dual antithrombotic did not cause any organ dysfunction.

In the RIVAL-PAD study, i.e., a Phase 2 study with 10 patients in RA group and 10 patients in the CA group, there were no significant baseline differences with respect to ABI (0.67 vs. 0.61, respectively) in the RA group and CA group.[4]

In the COMPASS study, compared with those participants randomized to aspirin alone, participants randomized to receive RA combination were less likely to suffer a MALE (2.6% vs. 1.5%; hazard ratios 0.57; 95% confidence interval [CI]: 0.37–0.88; P = 0.01). Total and major amputations were also reduced by 58% (95% CI: 15%–79%) and 67% (95% CI: 8%–88%), respectively.[5]

In the VOYAGER PAD study, the primary efficacy outcome with a composite of acute limb ischemia, major amputations for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes was 15.5% in the rivaroxaban group and 19.9% in the placebo group, with a significant difference with P = 0.009, with the individual outcomes of major amputation for vascular causes being 3.4% and 3.9%, myocardial infarction 4.0% and 4.5%, ischemic stroke 2.2% and 2.5%, death from cardiovascular causes 6.1% and 5.3% in the rivaroxaban and placebo group, respectively.[6]

In the COMPASS study, major bleeding was observed in 3.2% of the patients in rivaroxaban 2.5 mg bid plus aspirin 100 mg group, 3.1% in the rivaroxaban 5 mg bid monotherapy group, and 2.0% in the aspirin 100 mg monotherapy group, and severe bleeding leading to death or symptomatic bleeding into a critical organ or surgical site bleeding requiring re-operation was reported in 1.1% each in the rivaroxaban 2.5 mg bid plus aspirin 100 mg group while rivaroxaban 5 mg bid monotherapy group and 0.8% of patients reported severe bleeding in the aspirin 100 mg monotherapy group.[5]

In the VOYAGER PAD trial, which involved a broad population of patients who had undergone lower-extremity revascularization, nearly 1 in 5 patients in the placebo group had the primary composite outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes at 3 years. The addition of rivaroxaban at a dose of 2.5 mg twice daily to aspirin reduced this risk by approximately 15%.[6]

Together, these trials show the efficacy of rivaroxaban at a dose of 2.5 mg twice daily added to aspirin in PAD from its initiation after the lower-extremity intervention and continuing through long-term prevention.

In the present study, rivaroxaban (10 mg) with aspirin compared with standard DAPT (CA) proved to be equally effective in terms of primary and secondary outcomes, and no safety concerns were noted.


  Conclusion Top


This study was conducted with an intention to prospectively compare the efficacy and safety of RA when compared with CA (standard DAPT) following infrainguinal endovascular revascularization. The primary patency following endovascular revascularization is measured in terms of mean ABI, TcPO2 (supine/dependent). Significant improvement in ABI and TcPO2 in both the groups following endovascular procedure indicating successful revascularisation .No significant drop in ABI and TcPo2 values in followup period in both the groups indicating maintained patency. The dual antithrombotic therapy prevents the occurrence of MALE and MACE; there was no significant difference between the two groups and both regimens were equally efficacious. There was no major bleeding among patients in the two groups, with few patients presenting with minor bleeding in both the groups which indicated no safety concerns among the two groups. Wound healing was comparable between the two groups. The hemoglobin, serum creatinine, and LFT were measured and followed up between the two groups, and no significant difference between the two groups was noted indicating the safety of the regimen. The major limitations of the study were that the choice of antithrombotic was dependent on the operating vascular surgeon; hence, patients compared across the two groups were not randomized. The number of subjects included in the study was small in number and the duration of follow-up was short in the present study. Follow-up for longer period of time is required to measure the safety and efficacy. The dose of rivaroxaban used in this study was 10 mg, while approved and recommended dose in PAD is 2.5 mg/twice daily (due to nonavailability when the study was initiated). Both the antithrombotic regimens can be considered safe and efficacious in the post-OP management of patients undergoing infrainguinal revascularization; with maintenance of primary patency, comparable wound healing, incidence of MALE and MACE and safe in terms of complications like bleeding; and no impairment in the serum creatinine and liver function tests in the immediate post-OP period and during follow up. RA was equally efficacious and safe compared with CA group and hence can be used successfully in maintaining the primary patency, preventing MALE/MACE and having no safety concerns.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, et al. Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg 2007;45 Suppl S: S5-67.  Back to cited text no. 1
    
2.
Alonso-Coello P, Bellmunt S, McGorrian C, American College of Chest P. Antithrombotic therapy in peripheral artery disease: Antithrombotic therapy and prevention of thrombosis. 9th ed.: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e669S-90S.  Back to cited text no. 2
    
3.
Azarbal A, Clavijo L, Gaglia MA Jr. Antiplatelet therapy for peripheral arterial disease and critical limb ischemia: Guidelines abound, but where are the data? J Cardiovasc Pharmacol Ther 2015;20:144-56.  Back to cited text no. 3
    
4.
Jetty P, Kubelik D, Nagpal S. Rivaroxaban Plus Aspirin Versus Standard Dual Antiplatelet Therapy Following Angioplasty for Lower Extremity Peripheral Arterial Disease in Patients with Critical Limb Ischemia and Claudication (RIVAL-PAD): 12 Month Results of a Randomized Trial. Vol. 69. Abstracts from 2018 Canadian Society for Vascular Surgery Annual Meeting; 2019. p. e228.  Back to cited text no. 4
    
5.
Anand SS, Caron F, Eikelboom JW, Bosch J, Dyal L, Aboyans V, et al. Major adverse limb events and mortality in patients with peripheral artery disease: The COMPASS trial. J Am Coll Cardiol 2018;71:2306-15.  Back to cited text no. 5
    
6.
Bonaca MP, Bauersachs RM, Anand SS, Debus ES, Nehler MR, Patel MR, et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med 2020;382:1994-2004.  Back to cited text no. 6
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]



 

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