Heparin Dose and Harm: Absence of Evidence or Evidence of Absence?

There has been tremendous evolution in drug and device therapy for percutaneous coronary intervention (PCI) since its inception more than 3 decades ago. Although direct thrombin inhibitors, and to a lesser extent low molecular weight heparin, have eaten into the previous market dominance of unfractionated heparin (UFH) in the United States, the latter is still employed in a sizeable minority of contemporary PCI procedures. Despite its longstanding use for invasive diagnostic and therapeutic cardiovascular procedures, there are few conclusive data available to guide practitioners on selection of the appropriate UFH dose in these settings.

In this issue of the Journal of Invasive Cardiology, Arsanjani et al examine outcomes among 108 adult cardiac transplant recipients who underwent coronary artery intravascular ultrasound (IVUS) to exclude cardiac allograft vasculopathy using adjunctive low-dose UFH anticoagulation.¹ Following endomyocardial biopsy and coronary angiography but before IVUS, all patients were administered 2000-3000 units of UFH. Prior to common femoral artery sheath removal, all received protamine. The incidence of death, myocardial infarction (MI), coronary revascularization, or serious bleeding was ascertained retrospectively at 30 days; one procedure-related catheter-induced dissection occurred and required PCI. Although this study suggests that low-dose UFH anticoagulation may be adequate for preventing thrombotic events during IVUS, it was certainly underpowered to gauge the true impact of a low-dose UFH strategy on hard clinical events. The impact on surrogate markers of cardiac injury (eg, troponin) was also not assessed. What is apparent from this series is that performing surveillance IVUS is not an entirely benign procedure, regardless of the intensity of anticoagulation (0.93% risk of emergent PCI in this study, not dissimilar from the 1.6% rate of coronary dissection/perforation observed in the Providing Regional Observations to Study Predictors of Events in the Coronary Tree [PROSPECT] trial,² where patients underwent routine 3-vessel IVUS). This risk must be balanced against the theoretical benefit of identifying new stenotic coronary lesions in cardiac transplant patients.

The need for and ideal dosing of adjunctive UFH for invasive cardiovascular procedures has been the subject of numerous registry and randomized studies and remains an area of controversy.³ In a meta-analysis of 4 randomized controlled trials (RCTs; n = 8369) in which patients underwent PCI with adjunctive glycoprotein IIb/IIIa inhibition (GPI) in the majority, increasing UFH dose was associated with greater risk of hemorrhagic complications and there was no lower dose limit to this association; in contrast, no relationship between UFH dose and ischemic outcome was observed.⁴ Given the adverse short- and long-term outcome associated with hemorrhagic complications following PCI,⁵ it is not surprising that there have been numerous efforts to identify a UFH ‘floor,’ if not eliminate anticoagulation from the peri-PCI pharmacologic regimen altogether.

A number of investigators have compared fixed low-dose versus ‘standard’ weight-adjusted UFH. No significant difference in the incidence of in-hospital ischemic or hemorrhagic complications was observed in an all-comers cohort study (n = 500) comparing patients undergoing PCI treated with 5000 U versus 70 U/kg UFH (all received dual-antiplatelet therapy [DAPT] and a minority, a GPI).⁶ Similarly, another registry study (n = 698) of patients with stable angina undergoing elective transradial PCI for single-vessel disease, found no significant difference in the median troponin level or in the percentage of patients with a positive troponin when comparing those treated with 3000 U versus 70 U/kg UFH.⁷

Hoping to lower the UFH floor even further, 2 studies have examined the outcomes associated with ultra-low dose UFH administration for PCI. In a single-arm cohort study (n = 83) of non-emergent PCI patients administered DAPT, a GPI and UFH at 30 U/kg, no death, MI, or target vessel revascularization occurred out to 30 days; one minor bleed occurred and creatine kinase was 2x normal in 1 patient.⁸ In a second cohort study of patients undergoing PCI (recent MI and left main PCI excluded) (n = 418), in which most were not pretreated with DAPT and did not receive a GPI, the administration of UFH at 30 U/kg was associated with a 2.9% incidence of in-hospital death, MI, or repeat revascularization and 1 major vascular complication.⁹

Finally, observational and randomized studies have evaluated the possibility of performing ‘no dose’ PCI (ie, without UFH or other anticoagulants). In a large cohort study of patients undergoing elective PCI (n = 500) treated with DAPT and GPI but no UFH or other anticoagulant, the risk of MI was 1.6% while that for major and minor bleeding was 0.2% and 0.6%.¹⁰ In the Reduction in Major and Minor Adverse Events With Eptifibatide-based Pharmacotherapy in Percutaneous Coronary Intervention (REMOVE) RCT (n = 159), patients undergoing elective PCI with DAPT were randomized to GPI + 50 U/kg UFH versus GPI without UFH. Although those who underwent PCI without UFH had a significantly lower Landefeld bleeding index, there was no significant difference in the incidence of clinically manifest hemorrhagic complications, nor was a difference in ischemic event rates evident.¹¹ Finally, in the Coronary Interventions Antiplatelet-based Only (CIAO) RCT (n = 700), patients undergoing elective PCI of uncomplicated lesions were pretreated with DAPT ± GPI and randomized to 70-100 U/kg UFH versus no UFH.¹² Periprocedural CK-MB levels and postprocedure bleeding rates were higher among those who were treated with UFH.

In reviewing the totality of evidence along the spectrum from fixed low-dose, to ultra-low dose, to no-dose UFH, it is tempting to conclude that little to no anticoagulation is needed during invasive coronary procedures, at least in the setting of PCI for stable uncomplicated lesions. However, most of the above studies, even those that were randomized, were too small to detect significant differences in clinically relevant endpoints. Even when considered in aggregate (n = 4012), only 6 deaths, 58 MIs, 13 urgent revascularizations, and 6 minor or major bleeds were reported in these studies, hardly enough to allow one to discern whether a lower-dose UFH strategy is safe or effective. For now, the evidence-based operator would be wise to adhere to our latest societal guidelines and administer UFH at 50-70 U/kg with and 70-100 U/kg without adjunctive glycoprotein IIb/IIIa inhibitors (less if anticoagulation has been administered prior to the PCI procedure).¹³ As for the potential harm of administering adjunctive fixed low-dose UFH for IVUS or other invasive diagnostic cardiovascular procedures, it is just as true that ‘absence of evidence is not evidence of absence.’

References

1. Arsanjani R, Khitri A, Hashemzadeh M, Movahed MR. Low dose unfractionated heparin administration during intravascular ultrasound studies is safe even shortly after endomyocardial biopsy in cardiac transplant patients. J Invasive Cardiol. 2012;24(4):154-156.   
2. Stone GW, Maehara A, Lansky AJ, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2011;364(3):226-235.
3. Dauerman HL. Coronary intervention without a safety net. J Am Coll Cardiol. 2008;52(16):1299-1301.
4. Brener SJ, Moliterno DJ, Lincoff AM, et al. Relationship between activated clotting time and ischemic or hemorrhagic complications: analysis of 4 recent randomized clinical trials of percutaneous coronary intervention. Circulation. 2004;110(8):994-998.
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6. Kalapatapu K, Shao J, Aronow WS, et al. Prevalence of in-hospital complications in 500 patients undergoing percutaneous coronary intervention treated with heparin 5000 IU administered systemically versus 500 age-matched and sex-matched patients treated with heparin 70 IU/kg administered systemically. Am J Ther. 2010;17(6):E179-E181.
7. Kidambi A, Mayurathan G, Viswanathan G, Schechter C, Zaman AG. Unfractionated heparin during elective PCI: fixed dose or weight adjusted? Cardiovasc Ther. 2012;30(1):1-4.
8. Le May M, Kurdi M, Labinaz M, et al. Safety of coronary stenting with eptifibatide and ultra-low-dose heparin. Am J Cardiol. 2005;95(5):630-632.
9. Godon P, Rioufol G, Finet G, et al. [Efficacy and safety of low-dose heparin (30 IU/kg) during coronary angioplasty]. Arch Mal Coeur Vaiss. 2001;94(9):984-988.
10. Denardo SJ, Davis KE, Tcheng JE. Elective percutaneous coronary intervention using broad-spectrum antiplatelet therapy (eptifibatide, clopidogrel, and aspirin) alone, without scheduled unfractionated heparin or other antithrombin therapy. Am Heart J. 2005;149(1):138-144.
11. Valencia R, Price MJ, Sawhney N, et al. Efficacy and safety of triple antiplatelet therapy with and without concomitant anticoagulation during elective percutaneous coronary intervention (the REMOVE trial). Am J Cardiol. 2007;100(7):1099-1102.
12. Stabile E, Nammas W, Salemme L, et al. The CIAO (Coronary Interventions Antiplatelet-based Only) study: a randomized study comparing standard anticoagulation regimen to absence of anticoagulation for elective percutaneous coronary intervention. J Am Coll Cardiol. 2008;52(16):1293-1298.
13. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011;58(24):E44-E122.

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From the Michigan Heart & Vascular Institute, Ann Arbor, Michigan.
Disclosure: The author has completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The author reports no conflicts of interest regarding the content herein.
Address for correspondence: Herbert D. Aronow, MD, MPH, 5325 Elliott Dr., Ste. #202, Ypsilanti, MI 48197. Email: haronow@michiganheart.com. Twitter: @herbaronow.