Unfractionated heparin (UFH) has been the standard antithrombin agent since the early days of PCI and used as a reference against which new antithrombotic agents have been tested. Unfractionated heparin binds to antithrombin and augments the inactivation of thrombin and to a lesser extent factor Xa and IXa.

Despite its longstanding application, recommendations regarding UFH dose during PCI lack evidence base from large-scale, randomized clinical trials. Current dosing recommendations in Europe are 70–100 U/kg i.v. bolus and 50–70 U/kg i.v. bolus if GP IIb/IIIa inhibitors are co-administered [32]. The ACC/AHA guideline committee recommends the same initial bolus dose but also recommends that subsequent doses be guided according to activated clotting time (ACT), to achieve 250–300 s for HemoTec and 300–350 s for Hemochron device and a target ACT of 200–250 s in case of GPIIb/IIIa co-administration [64]. Yet, the value of ACT guidance has been discussed controversially.

Several studies suggest increased sensitivity of women to heparin. Partial thromboplastin time (PTT) after heparin is longer in women compared to women, even after weight-adjusted dosing [65, 66]. Moreover, women have a nearly fivefold increased risk of heparin-induced thrombocytopenia [67].

Compared to UFH, low molecular weight heparin (LMWH) has a higher ratio of anti-factor Xa compared to anti-factor IIa activity and therefore a greater proximal inhibition of the coagulation cascade. Advantages of LMWH over UFH include a more stable and predictable anticoagulant effect, obviating the need for routine monitoring, less platelet activation, and a lower incidence of HIT. Disadvantages in case of bleeding include the lack of complete reversibility with protamine and a long half-life.

Studies on the pharmacodynamic response according to gender have yielded conflicting results. In a substudy of the open-label TIMI 11A trial, comparing 2 different doses of enoxaparin in 445 NSTE-ACS patients (36 % women), found comparable results for anti Xa activity according to gender [68]. On the other hand, a substudy of the double-blind FRISC trial, comparing dalteparin against placebo in 175 patients with NSTE-ACS (25 % women), found higher anti X activity in women compared with men [69]. Consistent with this finding, there was a large reduction in the primary endpoint of death or MI at 6 days in women enrolled in the main FRISC trial (RR women 0.16, 95 % CI 0.05–0.56, RR men 0.55, 95 % CI 0.28–1.11, p values for interactions were not reported) [70].

The value of LMWH in patients undergoing elective PCI was assessed in the open-label STEEPLE trial. In that study, 2 doses of enoxaparin (0.5 and 0.75 mg/kg bodyweight) were compared against UFH. Bleeding according to study definition and GUSTO moderate or severe bleeding (but not TIMI major or minor bleeding) was reduced with the use of the low but not of the high dose of enoxaparin. Yet, enrolment in the low-dose arm was stopped prematurely due to increased mortality. The trial was not sufficiently powered for the assessment of ischemic events. In a multivariate analysis, female gender was an independent predictor for bleeding (HR 1.63, 95 % CI 1.23–2.17). Gender-specific data were not reported [71].

Superiority of LMWH over UFH has been shown in clinical trials of patients with NSTE-ACS receiving conservative treatment [72] and in STEMI patients treated with fibrinolysis [73]. The ExTRACT-TIMI 25 trial compared LMWH with UFH in 20,506 STEMI patients receiving fibrinolysis. In a gender-specific analysis (4,783 women), the relative risk reduction in the primary endpoint of death or nonfatal recurrent MI in women was comparable to that achieved in men (RR women 0.82, 95 % CI 0.74–0.90; RR men 0.84, 95 % CI 0.74–0.95). Due to a higher risk profile, the absolute benefit was higher in women (2.9 % versus 1.9 %). The rate of bleeding was higher with LMWH compared to UFH in the overall population and in women. The rate of bleeding in women and men receiving enoxaparin was comparable [74].

The value of LMWH in the revascularization era with the use of stents and adjunct antithrombotic therapy has diminished. In clinical trials – such as the SYNERGY trial of 10,027 patients with NSTE-ACS (34 % women) – in which prerandomization antithrombotic therapy was not consistent with study treatment and high post-procedural crossover rates, LMWH was not superior to UFH but increased the risk of bleeding [75]. In general, crossover between UFH and LMWH is not recommended and should be avoided [76]. In the SYNERGY trial, no significant interaction for gender and treatment effect regarding the composite of death or MI at 30 days was observed [75].

The value of LMWH compared to UFH in STEMI patients undergoing PCI has been assessed in the open-label ATOLL trial [77]. Among 910 patients, the primary endpoint of death, MI, procedural failure, or major bleeding at 30 days was numerically lower in patients assigned to LMWH, but the benefit was not statistically significant (p = 0.06). However, there was a significant benefit with LMWH regarding the secondary composite endpoint of death, recurrent ACS, and urgent revascularization and in the primary endpoint when data were analyzed according to per protocol analysis [78]. Subgroup analysis did not find significant heterogeneity for the primary and secondary outcome according to gender. In women, results were directionally the same compared to men [77].

Bivalirudin is a synthetic direct thrombin inhibitor with several theoretic advantages over unfractionated heparin: greater thrombin specificity, linear kinetic, shorter half-life, lack of platelet activation, and heparin-induced thrombocytopenia and action on clot bound and circulating thrombin.

Bivalirudin has been suggested as a replacement for heparin as antithrombotic agent during PCI due to reduced bleeding rates (at least compared to a combination of heparin plus glycoprotein IIb/IIIa inhibitors and high heparin doses) while providing similar protection from peri-procedural ischemic complications. Since women are more susceptible to bleeding, the use of bivalirudin seems particularly attractive in this population.

Subgroup analyses of the pivotal bivalirudin trials ACUITY [79], REPLACE-2 [80], and HORIZONS-AMI [81] did not find a significant interaction for gender and treatment effect regarding composite ischemic, bleeding, and net clinical endpoints.

Also in the randomized ISAR-REACT 3 and 4 trials comparing bivalirudin against heparin monotherapy in biomarker-negative patients [82] and bivalirudin against heparin plus abciximab in NSTEMI patients [83], no interaction of gender with treatment effect was observed.

A more refined analysis of the ISAR-REACT 3 trial of biomarker-negative patients aimed to identify subsets of patients at high risk of bleeding or myocardial infarction and to investigate whether such high-risk subsets derive preferential benefit from heparin or bivalirudin. Bivalirudin was found to be most advantageous in reducing the risk of bleeding in patients at low risk, such as younger patients, men, patients with greater body weight, and those with single lesion intervention. Bivalirudin was not helpful in reducing the risk of bleeding in subsets of patients at a higher risk for this event. Moreover, the use of bivalirudin in the subgroup of patients with low bleeding risk was associated with a trend towards an increased risk of myocardial infarction [84].

Fondaparinux – a synthetic pentasaccharide – indirectly inhibits factor Xa via binding to antithrombin III.

In the double-blind OASIS 6 trial of 12,092 STEMI patients (3,345 women), the benefit of fondaparinux was limited to patients receiving thrombolysis or no reperfusion therapy. In patients undergoing primary PCI, fondaparinux was associated with potential harm. There was an increased risk of guiding catheter thrombosis and subsequent coronary complications with fondaparinux [85]. The results of death or myocardial infarction were not significantly heterogeneous in women and men.

In the double-blind OASIS 5 trial of 20,078 patients (7,699 women) with NSTE-ACS, the use of fondaparinux over 6 days was noninferior to enoxaparin regarding the composite ischemic endpoint of death, myocardial infarction, or refractory ischemia at 9 days. The rate of major bleeding was significantly lower with fondaparinux, resulting in improved net clinical benefit and decreased mortality at 30 and 180 days. Results for the primary efficacy endpoint and the safety endpoint of major bleeding were consistent in women and men (primary efficacy endpoint: women RR 1.08, 95 % CI 0.89–1.30, men RR 0.97, 95 % CI 0.83–1.12, p interaction = 0.48; major bleeding women RR 0.46, 95 % CI 0.34–0.58, men RR 0.61, 95 % CI 0.49–0.76, p interaction = 0.07) (Table 6.2).