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Shahzad A, et al. "Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial.". The Lancet. 2014. 384(9957):1849-1858.
PubMedFull text

Clinical Question

In patients with STEMI undergoing PCI, is peri-procedural bivalirudin associated with reduced bleeding or thrombotic events when compared to heparin?

Bottom Line

In patients with STEMI undergoing PCI on ASA and P2Y12 inhibitors with GP IIb/IIIa inhibitor use reserved for bailout, bivalirudin was associated with 50% increase in the primary outcome of death, CVA, new or recurrent MI, and unplanned revascularization when compared to heparin. The difference was driven primarily by a 2% absolute reduction in new or recurrent MI and unplanned revascularization.

Major Points

The first contemporary trial addressing the performance of anticoagulation with bivalirudin vs. heparin in the STEMI population was HORIZONS-AMI trial [1], which demonstrated a 40% reduction in risk for major bleeding with bivalirudin with a 1% absolute increase in acute stent thrombosis. These conclusions were limited by trial design which mandated use of IV glycoprotein IIb/IIIa inhibitors in the heparin group only making it unclear whether these differences were driven solely by IIb/IIIa inhibitor effect. The subsequent EUROMAX[2] trial showed very similar results to HORIZONS-AMI but also suffered from asymmetry in IIb/IIIa inhibitor use between arms.

The HEAT-PPCI trial was designed to confirm the relative safety and efficacy of anticoagulation with bivalirudin vs. heparin in the STEMI population in the contemporary PCI setting in which IIb/III inhibitor use is relatively uncommon and generally reserved only for high-risk lesions ("bailout" therapy). HEAT-PPCI demonstrated that in patients presenting with STEMI being treated universally with ASA and P2Y12 antagonists with GP IIb/IIIa use reserved solely for bailout, heparin was associated with a 2% absolute risk reduction in new or recurrent MI as well as a 2% reduction in unplanned revascularization at 28 days. Bleeding rates were similar in both groups. GP IIb/IIIa inhibitor use was low and nearly identical in both groups (13 in heparin group and 15% in bivalirudin group). The trial was also notable for its strategy of delayed informed consent, which allowed for 97% recruitment of eligible patients and increased the generalizability of these results.

Prior to HEAT-PPCI, the prevailing notion informing clinical practice was that bivalirudin reduced bleeding complications at the cost of higher acute stent thrombosis rates. HEAT-PPCI provided strong evidence against this idea by demonstrating equal bleeding rates while confirming decreased thrombotic protection. As a result, bivalirudin use is now far less common in the setting of primary PCI and arguably should be utilized only in patients with intolerance to heparin. Notably, the 2013 ACCF/AHA guidelines which have not been updated since before HEAT-PPCI still recommend bivalirudin as an acceptable option for anticoagulation in primary PCI and state that it is reasonable to prefer bivalirudin over the combination of UFH and IIb/IIIa inhibitor in patients at high risk of bleeding.


2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction (adapted) [3]

  • For patients with STEMI undergoing primary PCI, the following supportive anticoagulant regimens are recommended:
    • UFH, with additional boluses administered as needed to maintain therapeutic activated clotting time levels, taking into account whether a GP IIb/IIIa receptor antagonist has been administered (Class I, Level of Evidence C).
    • Bivalirudin with or without prior treatment with UFH (Class I, Level of Evidence B).
  • For patients with STEMI undergoing PCI who are at high risk of bleeding, it is reasonable to use bivalirudin monotherapy in preference to the combination of UFH and a GP IIb/IIIa receptor antagonist (Class IIa, Level of Evidence B).


  • Single center, open-label, blocked-randomized, controlled trial
  • N=1812
    • Bivalirudin (n=905)
    • Heparin (n=907)
  • Setting: 1 center in UK
  • Enrollment: February 2012 to November 2013
  • Mean follow-up: 28 days
  • Analysis: Intention-to-treat
  • Primary efficacy outcome: All cause mortality, CVA, reinfarction, or additional unplanned target revascularization.
  • Primary safety outcome: Major bleeding at 28 days (BARC 3-5)


Inclusion Criteria

  • > 18 years old
  • Presentation for emergent catheterization for suspected STEMI

Exclusion Criteria

  • Known intolerance, hypersensitivity, or contraindication to bivalirudin or heparin
  • Active bleeding at presentation
  • Artificial ventilation
  • Reduced consciousness precluding administration of PO medication
  • Contraindication to antiplatelet loading
  • Previous enrollment in the trial

Baseline Characteristics

Comparisons are bivalirudin vs. heparin, respectively

  • Mean age (years): 62.9 vs. 63.6
  • Female sex (%): 29 vs. 27
  • White race (%): 96 vs. 96
  • Median body weight (kg): 80 vs. 80
  • Diabetes (%): 13 vs. 15
  • HTN (%): 40 vs. 43
  • Hyperlipidemia (%): 37 vs. 38
  • Family History of coronary disease (%): 44 vs. 45
  • Current smoker (%): 42 vs. 43
  • Previous MI (%): 14 vs. 10
  • Previous PCI (%): 8 vs. 6
  • Previous CABG (%): 2 vs. 2
  • Median symptom onset to randomization time (hours): 2.8 vs. 2.8
  • ASA use (%): 99 vs. 99
  • P2Y12 inhibitor load use (%): 99 vs. 99
  • IIb/IIIa inhibitor use (%): 13 vs. 15
  • Access Site
    • Femoral (%): 19 vs. 18
    • Radial (%): 80 vs. 82
  • Activated Clotting Time
    • 5-15 minutes after bolus dose (s): 251 vs. 224
    • At end of procedure (s): 246 vs. 206
  • PCI performed (%): 83 vs. 82
  • Stent implanted (%): 93 vs. 92
  • DES implanted (%): 80 vs. 80
  • TIMI III flow achieved (%): 93 vs. 93
  • LVEF
    • >= 55%: 44 vs. 45
    • 45%-54%: 26 vs. 25
    • 36%-44%: 20 vs. 20
    • <=35%: 10 vs. 9
  • Medications at discharge
    • ACE inhibitor (%): 84 vs. 86
    • Beta blocker (%): 86 vs. 87
    • ASA (%): 94 vs. 95
    • P2Y12 inhibitor (%): 89 vs. 88
    • Statin (%): 90 vs. 91


  • Randomized to bivalirudin (0.75mg/kg bolus followed by 1.75mg/kg/h) or heparin (70U/kg initial bolus with repeat bolus for ACT<200) for primary PCI
    • Randomization stratified by age (< 75 years vs. >= 75 years) and by presence/absence of cardiogenic shock
  • All patients received ASA and P2Y12 inhibition before primary PCI
  • IIb/IIIa inhibitor use reserved for bailout (evidence of massive thrombus, no- or slow-reflow, or thrombotic complication)
  • Patient case notes and electronic records were examined by trial investigators throughout the course of index admission and up to 28 days for primary and secondary outcome measures
  • Patient reports were also crosschecked against national mortality data tracking
  • All primary efficacy and safety outcome measures and stent thrombosis were assessed by an independent Clinical Events Committee


Comparisons are bivalirudin vs. heparin. * Indicates statistically significant difference.

Primary Outcomes

Death, CVA, New or Recurrent MI, or Unplanned Revascularization
8.7% vs. 5.7% (HR 1.52; 95% CI 1.09-2.13; P=0.01)
BARC 3-5 Major Bleeding
3.5% vs. 3.1% (HR 1.15; 95% CI 0.70-1.89; P=0.59)

Secondary Outcomes

5.1% vs. 4.3% (HR 1.18; 95% CI 0.78 to 1.79; P=0.43)
1.6% vs. 1.2% (HR 1.37; 95% CI 0.63-2.96; P=0.43)
New or Recurrent MI
2.7% vs. 0.9% (HR 3.01; 95% CI 1.36-6.66; P=0.004)
Unplanned Revascularization
2.7% vs. 0.7% (HR 4.01; 95% CI 1.65-9.76; P=0.02)
Stent Thrombosis
3.4% vs. 0.9% (HR 3.91; 95% CI 1.61-9.52; P=0.001)
CK-MB Post-Procedure
97 vs. 106 (P=0.55)

Subgroup Analysis

All Comparisons are for Primary Outcome

Access Site (Interaction P=0.48)
Radial: 8.7% vs. 5.7%
Femoral: 11.7% vs. 9.9%
Diabetes (Interaction P=0.35)
Yes: 17.7% vs. 8.0%
No: 7.4% vs. 4.8%
Age (Interaction P=0.11)
>=75: 14.8% vs. 13.5%
<75: 7.0% vs. 3.5%
P2Y12 Drug Used (Interaction P=0.78)
Clopidogrel: 10.3% vs. 7.7%
Prasugrel: 6.9% vs. 3.6%
Ticagrelor: 8.7% vs. 6.2%
LVEF Impaired (Interaction P=0.67)
Yes: 9.9% vs. 7.7%
No: 3.0% vs. 1.9%
PCI Attempted (Interaction P=0.88)
Yes: 8.4% vs. 5.4%
No: 10.4% vs. 7.2%

Adverse Events

Any Bleed
12.5% vs. 13.5% (HR 0.93; 95% CI 0.73-1.18; P=0.54)
Minor Bleed
9.2% vs. 10.8% (HR 0.85; 95% CI 0.64-1.12; P=0.25)
8.3% vs. 7.3% (HR 1.13; 95% CI 0.80-1.61; P=0.49)


  • Single-center study involving a teriary care center with a population that was 95% white, limiting generalizability.
  • Open-label design allows for potential bias although all events were subject to masked assessment.
  • Bleeding rates significantly lower than those in the EUROMAX[2] and HORIZONS-AMI[1] studies likely due to less IIb/IIIa inhibitor use, limiting power for detection of differences in bleeding risk.


The study was partially funded by unrestricted grants from The Medicines Company and AstraZeneca but these companies had no role in study design, conduct, or reporting.

Further Reading

  1. 1.0 1.1 Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218-30.
  2. 2.0 2.1 Bivalirudin started during emergency transport for primary PCI. N Engl J Med 2013;369:2207-17
  3. 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction. Circulation 2013;127:00-00