No More Heparin for NSTEMI?

Background: The 2014 AHA guidelines for the management of NSTEMI, recommend unfractionated heparin with an initial loading dose of 60IU/KG (maximum 4,000 IU) with an initial infusion of 12 IU/kg/hr (maximum 1,000 IU/hr) adjusted per active partial thromboplastin time to maintain therapeutic anticoagulation according to the specific hospital protocol, continued for 48 hours or until PCI is performed (Level of Evidence B) [2]. With even a higher level of evidence the 2014 AHA guidelines for the management of NSTEMI, also recommend enoxaparin 1mg/kg subcutaneously every 12 hours with reduced dosing to 1mg/kg subcutaneously in patients with a creatinine clearance <30mL/min) (Level of Evidence A) [2].  The studies supporting this therapy were performed primarily on patients with a diagnosis of unstable angina and in the era before dual anti platelet therapy and early catheterization/revascularization. Therefore, the authors of this paper looked to evaluate the clinical outcomes associated with parenteral anticoagulation therapy (Heparin) in the era of dual anti-platelet therapy in patients with NSTEMI.

What They Did:

• Evaluate the association between parenteral anticoagulation therapy and clinical outcomes in patients with non-ST-segment elevation undergoing percutaneous coronary intervention at 5 medical centers in China
• Retrospective cohort study
• Parenteral Anticoagulation Therapy = Anticoagulation prior to PCI (Unfractionated Heparin)
• No Parenteral Anticoagulation Therapy = Only receiving anticoagulation during PCI (Low molecular weight heparin or Fondaparinux)

Outcomes:

• Primary:
  • In-hospital all-cause mortality
  • In-hospital major bleeding
• Secondary:
  • Any bleeding
  • Myocardial infarction
  • Composite outcome of death or myocardial infarction
  • Composite outcome of death, myocardial infarction, or major bleeding in hospital
  • Composite outcome of death or major bleeding during follow-up

Inclusion:

• Adult patients, in China, with NSTEMI, receiving parenteral anticoagulation prior to percutaneous coronary intervention

Exclusion:

• Only receiving parenteral anticoagulation therapy after percutaneous coronary intervention
• Pregnant
• Cardiogenic shock requiring intra-aortic balloon pump
• Other indications for anticoagulation

Results:

• 8197 patients underwent percutaneous coronary intervention
  • 6804 patients met the final criteria for inclusion in the study
    • 3901 patients (57.3%) had confirmed NSTEMI
    • 2903 patients (42.7%) had unstable angina
    • Dual antiplatelet therapy was given to 6590 patients (96.9%)
      • 6504 (98.7%) of these patients received this therapy prior to diagnostic catheter placement
    • In-Hospital Mortality:
      • Parenteral Anticoagulation: 0.3%
      • No Parenteral Anticoagulation: 0.1%
      • P = 0.13
      • aOR 1.27; 95% CI 0.38 – 4.27; P = 0.70
    • Myocardial Infarction:
      • Parenteral Anticoagulation: 0.3%
      • No Parenteral Anticoagulation: 0.3%
      • P = 0.82
      • aOR 0.77; 95% CI 1.24 – 3.03; p = 0.004
    • In-Hospital Major Bleeding:
      • Parenteral Anticoagulation: 2.5%
      • No Parenteral Anticoagulation: 1.0%
      • P <0.001
      • aOR 1.94; 95% CI 1.24 – 3.03; p = 0.004
    • Composite Outcome of Death, MI, or Major Bleeding:
      • Parenteral Anticoagulation: 3.0%
      • No Parenteral Anticoagulation: 1.4%
      • P < 0.001
      • aOR 1.54; 95% CI 1.04 – 2.30; p = 0.03
    • Long Term Follow Up (Median 2.96 Years):
      • Death:
        • No Difference (aHR 0.87; 95% CI 0.71 – 1.07; p = 0.19)
      • Major Bleeding
        • Patients in parenteral anticoagulation group had higher risk (aHR 1.43; 95% CI 1.01 – 2.02; p = 0.04) compared to no parenteral anticoagulation (Most bleeding occurred in first 30 days)

Strengths:

• First study to evaluate association between parenteral anticoagulation therapy and clinical outcomes in patients undergoing PCI for NSTEMI in the era of dual antiplatelet therapy and PCI
• Data pertaining to antithrombotic therapy, such as parenteral anticoagulation, dual antiplatelet therapy dosages, dates of prescriptions, and durations of therapy were collected.
• All adverse clinical events were evaluated by an independent clinical events committee that was blinded to treatment details
• The dosage of low molecular weight heparin SQ was decreased among patients with creatinine clearance <30mL/min
• Secondary outcomes were pre-specified
• Enrolled consecutive patients
• The CRUSADE score (risk of major in-hospital bleeding) was equal between groups (42.39 vs 42.34), meaning both groups had equal chance of in-hospital major bleeding

Limitations:

• Retrospective study design has the obvious implications of only being able to report what was recorded in the chart. We don’t know why some patients got heparin and others did not. Perhaps those who got heparin were sicker by some measure, so clinicians were more aggressive.  This could bias the study to no difference.
• Unclear if data extractors were blinded
• For events that occurred more than once, only the index event was used for statistical analysis, which may underestimate events
• Patients who received parenteral anticoagulation therapy before PCI were classified into the parenteral anticoagulation group and patients who received parenteral anticoagulation therapy during PCI were classified in to the no parenteral anticoagulation therapy. This may minimize the actual results as both patient groups received anticoagulation therapy
• The type and duration of non-parenteral anticoagulation therapy was at the discretion of the clinician (fondaparinux or low molecular weight heparin SQ)
• Groups were not equally balanced. Patients in the parenteral anticoagulation therapy arm had higher GRACE scores (132.14) vs patients in the no parenteral anticoagulation therapy arm (123.97), meaning that the patients with parenteral anticoagulation had an increased risk of death at 6 months
• Patients mean weight was 65kg (145lbs) which may not generalize to our larger patient population in the US or other parts of the world. Our patients would get even higher doses of parenteral anticoagulation therapy.
• Most of the patients included in this study were classified as low-moderate risk, which might underestimate the efficacy of parenteral anticoagulation therapy
• There was a low event rate, which means this study had insufficient power to exclude substantial associated increase in the risk of death or MI
• Only included patients undergoing PCI, therefore the findings may not be generalized to all patients with NSTEMI

Discussion:

• All but three patients received unfractionated heparin at a bolus dose of 70 – 100U/kg (3 patients received bivalirudin)
• The majority of patients received low molecular weight heparin (79.1%)
• The median duration of parenteral anticoagulation therapy was about 6 days (Range 4 – 9 days)
• The authors used the CRUSADE score to assess the risk of bleeding. This score ranges from 1 – 96, with higher scores indicating higher risk of bleeding. The mean score was 42.35 in this patient population which equates to an about 10% risk of in-hospital major bleeding (NNH = 10).
• The authors also used the GRACE score to predict risk of death. This score ranges from 15 – 330.  This patient cohort had a mean GRACE score of 126.60 which equates to an about 10% risk of death at 10 months.
• Now that PCI is more widely used to prevent ischemic events, the protective effect of parenteral anticoagulation therapy may be less significant than before

Author Conclusion: “In the patients undergoing percutaneous coronary intervention for non-ST-segment elevation acute coronary syndrome, parenteral anticoagulation therapy was not associated with a lower risk of all-cause death or myocardial infarction but was significantly associated with a higher risk of major bleeding.  These findings raise important safety questions about the current practice of routine parenteral anticoagulation therapy while we await randomized trials of this practice.”

Clinical Take Home Point: Parenteral anticoagulation therapy did not decrease mortality in patients with NSTEMI undergoing PCI but did have more bleeding events compared to non-parenteral anticoagulation therapy. As this is a retrospective review, which has methodological limitations, the findings of this study should be considered hypothesis generating, urging the need for RCTs.

At this point in time, with no mortality benefit and increased bleeding risk, I would recommend holding off on parenteral anticoagulation therapy in UA/NSTEMI until I have had a discussion with my consultant about their preference of anticoagulation prior to PCI.

References:

1. Chen, JY et al. Association of Parenteral Anticoagulation Therapy With Outcomes in Chinese Patients Undergoing Percutaneous Coronary Intervention for Non-ST-Segment Elevation Acute Coronary Syndrome. JAMA Intern Med 2018. PMID: 30592483
2. Amsterdam EA et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. JACC 2014. PMID: 25260718

For More Thoughts on This Topic Checkout:

• First10EM: Heparin for Acute Coronary Syndrome: An Evidence Review
• EM Cases: Journal Jam 16 – Heparin for ACS and STEMI

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)