Fondaparinux: A cornerstone drug in acute coronary syndromes

Table 1 Comparison of unfractionated heparin, low molecular weight heparins (Enoxaparin), and Fondaparinux

	UFH	Enoxaparin	Fondaparinux
Source	Biological	Biological	Synthetic
Bioavailability	30%	90%	100%
Mechanism	Augments AT effects on Factor Xa and thrombin. Binds to plasma proteins not specifically → unpredictable dose-response	Augments AT effects more on Factor Xa than on thrombin. Low binding to plasma proteins → more predictable dose-response, low inter-patient variability	Augments anti-Xa activity of AT, no direct effect on thrombin. Specific for AT → no binding to other plasma proteins, predictable dose-response
Plasma half-life	1-2 h	4.5-7 h	17-21 h
Reversal agents	Protamine sulfate	Protamine sulfate	Irreversible by protamine factor VII- limited data
Routine monitoring	Yes	No	No
Dosing frequency in ACS	Treatment - Continuous i.v. infusion	BID	Once daily
Clearance	Hepatic & Reticuloendothelial clearance. No renal adjustments	Renal	Renal
		Adjustment needed for CrCl < 30 mL/min	Contraindication: CrCl < 30 mL/min
Ability to cause HIT	Yes	Yes	No cases in major trials
Bleeding risk	Increased	Increased	Lesser

UFH: Unfractionated heparin; HIT: Heparin-induced thrombocytopenia; AT: Antithrombin; ACS: Acute coronary syndrome; LMWH: Low molecular weight heparin.

Table 2 Organization to Assess Strategies in Ischemic Syndromes 5: Primary efficacy and safety outcomes at 9 d

Outcomes	Fondaparinux	Enoxaparin	HR (95%CI)	P value
Primary efficacy outcome: Cumulative event rate-Death, MI, refractory ischemia at 9 d
Cumulative event rate	5.80%	5.70%	1.01 (0.90-1.13)	0.007
Primary safety outcome: Major bleeding at 9 d
Major bleeding	2.20%	4.10%	0.52 (0.44-0.61)	P < 0.001

CI: Confidence interval; HR: Hazard ratio.

Table 3 Organization to Assess Strategies in Ischemic Syndromes 5: Fondaparinux vs Enoxaparin in non-ST elevation acute coronary syndrome patients undergoing percutaneous coronary intervention

Outcome day 9	Enoxaparin (n = 3072)	Fondaparinux (n = 3106)	Hazard ratio	P value
Death, MI, or stroke	6.2	6.3	1.03	0.79
Major bleeding	5.1	2.4	0.46	< 0.00001
Catheter thrombosis	0.4	0.9	3.59	0.001

MI: Myocardial infarction.

Table 4 Fondaparinux with unfractionated heparin during revascularization in acute coronary syndromes 8: Primary outcomes at 48 h

Primary outcomes at 48 h	Standard dose UFH (n = 1002)	Low dose UFH (n = 1024)	Odds ratio	95%CI	P value
Peri-PCI major, minor, bleeds and vascular access complications	5.80%	4.70%	0.80	0.54-1.19	0.27
Components
Major bleeds	1.20%	1.40%	1.14	0.53-2.49	0.73
Minor bleeds	1.70%	0.70%	0.40	0.16-0.97	0.04
Major vascular access site complications	4.30%	3.20%	0.74	0.47-1.18	0.21

UFH: Unfractionated heparin; CI: Confidence interval; PCI: Percutaneous coronary intervention.

Table 5 Fondaparinux with unfractionated heparin during revascularization in acute coronary syndromes 8: Secondary outcomes at 30 d

Secondary outcomes at 30 d	Standard dose UFH (n = 1002)	Low dose UFH (n = 1024)	Odds ratio	95%CI	P value
Peri-PCI major bleeding, Death, MI, TVR	3.90%	5.80%	1.51	1.00-2.28	0.05
Death, MI, TVR	2.90%	4.50%	1.58	0.98-2.53	0.06
Death	0.60%	0.80%	1.31	0.45-3.78
MI	2.50%	3.00%	1.22	0.72-2.08
TVR	0.30%	0.90%	2.95	0.80-10.9
Stent thrombosis	0.50%	1.20%	2.36	0.83-6.73	0.11
Catheter thrombosis	0.10%	0.5%	4.91	0.57-42.1	0.15

UFH: Unfractionated heparin; CI: Confidence interval; PCI: Percutaneous coronary intervention; TVR: Target vessel revascularization.

Table 6 Fondaparinux with unfractionated heparin during revascularization in acute coronary syndromes 8: Comparison to Organization to Assess Strategies in Ischemic Syndromes 5 major bleeding (< 48 h of percutaneous coronary intervention)

Adjusted major bleeding rate	OASIS 5 PCI	OASIS 5 PCI
	Fondaparinux	Enoxaparin
	Major bleeding	Major bleeding
FUTURA	1.5%	3.6%
Standard dose UFH 1.1% (0.6-2.1)
FUTURA
Low dose UFH 1.2% (0.6-2.2)

PCI: Percutaneous coronary intervention; FUTURA: Fondaparinux with unfractionated heparin; OASIS: Organization to Assess Strategies in Ischemic Syndromes; UFH: Unfractionated heparin.

Table 7 Primary efficacy outcome of Fondaparinux vs unfractionated heparin (control) in preventing death or reinfarction at 30 d and 3 or 6 mo and relative risk reduction of fondaparinux vs control through study end

Measures	Fondaparinux	Control (UFH)
Primary composite outcome: Death or reinfarction
Frequency at 30 d	9.70%	11.20%
P value	P = 0.008
Relative risk reduction	14%
Frequency at 9 d	7.40%	8.90%
P value	P = 0.003
Relative risk reduction	17%
Frequency at 3-6 mo	13.40%	14.80%
P value	P = 0.008
Relative risk reduction	12%

UFH: Unfractionated heparin.

Table 8 Subgroup analysis Organization to Assess Strategies in Ischemic Syndromes 6, n

OASIS 6	Stratum I		Stratum II		Total
	Placebo	Fondaparinux	UFH	Fondaparinux
	2835	2823	3221	3213	12092
Non-fibrin specific thrombolytic	2216	2179	83	83	4561
Fibrin specific thrombolytic	9	11	436	419	875
Any thrombolytic	2225	2190	519	502	5436

The number of patients who received thrombolytic therapy. OASIS: Organization to Assess Strategies for Ischemic Syndromes; UFH: Unfractionated heparin.

Table 9 Comparative studies between low molecular weight heparin/enoxaparin and fondaparinux

Name of study	Type of study	No of patients	Endpoints	Results	Conclusions
Comparative efficacy and safety of anticoagulant strategies for acute coronary syndromes	Network metanalysis of 42 randomized controlled trials	117353	Death, MI, revascularization, bleeding	Death and MI rates with Fondaparinux were lower than that with 5 other anticoagulant regimens. [UFH + glycoprotein IIb/IIIa inhibitor (GPI), UFH ± GPI, Bivalirudin, LMWH, and Otamixaban (a direct Factor Xa inhibitor)].	Fondaparinux had the most balanced profile compared to other evaluated strategies, ranking high for both efficacy and safety.
Comparison between Fondaparinux and low molecular-weight heparin in patients with acute coronary syndrome	Meta-analysis	62900	MACE, mortality, major bleeding events	Fondaparinux had significantly lower rates of MACE and major bleeding events. Lower all-cause mortality (-16%) vs LMWH.	In this meta-analysis of head-to-head comparisons, fondaparinux-based regimens presented advantages in MACE and major bleeding, as well as a net clinical benefit, compared with LMWH.
Choosing between Enoxaparin and Fondaparinux for the management of patients with acute coronary syndrome: A systematic review and meta-analysis	Meta-analysis	9618	Mortality, MI, Stroke, Minor/Major and all bleeding	Fondaparinux resulted in significantly lower bleeding rates during short-term (10 d) and long-term (30 d or 6 mo to 1 yr) intervals.	Fondaparinux could be a better option vs Enoxaparin, especially in NSTEMI patients, in terms of short to mid-term bleeding risk.
Comparison of Efficacy, Safety and Hemostatic Parameters of Enoxaparin and Fondaparinux in unstable coronary artery disease	Prospective, comparative study	180	Recovery, recurrence, major and minor bleeding	Recurrent MI or angina numerically more in the Enoxaparin group. At 30 d, enoxaparin showed a higher incidence of hemorrhage than fondaparinux (P < 0.05).	Fondaparinux appears to be better than enoxaparin in efficacy. Fondaparinux also has a better safety profile. Therefore, Fondaparinux is an attractive option compared to Enoxaparin in NSTE-ACS patients.

MACE: Major adverse cardiac–events; NSTE-ACS: Non-ST elevation acute coronary syndrome; UFH: Unfractionated heparin; LMWH: Low molecular weight heparin; GP: Glycoprotein; GPI: GP inhibitor; NSTEMI: Non-ST segment elevation myocardial infarction.

Table 10 Guideline recommendations for fondaparinux in acute coronary syndrome patients

AHA/ACC 2014	SC Fondaparinux for the duration of hospitalization or until PCI is performed.	2.5 mg s.c. daily	IB
ESC 2015	Fondaparinux is recommended as having the most favorable efficacy – safety profile regardless of the management strategy. In patients on Fondaparinux (2.5 mg s.c. daily) undergoing PCI, a single i.v. bolus of UFH (70-85 IU/kg, or 50-60 IU/kg in the case of concomitant use of glycoprotein IIb/IIIa inhibitors) is recommended during the procedure.	2.5 mg s.c. once daily	IB
NICE 2010	Fondaparinux is offered to patients who do not have a high bleeding risk (unless coronary angiography is planned within 24 h of admission). It should not be used in patients with significant renal dysfunction (those with a serum creatinine > 265 μmol/L were excluded from the trial).	2.5 mg s.c. once daily	NA
SIGN 2016	When there are ischemic electrocardiograph changes or elevation of cardiac markers, treat immediately with Fondaparinux. Continue for 8 d, or until hospital discharge or coronary revascularization.	2.5 mg s.c. once daily	1++
CPG Malaysian guidelines 2011	Fondaparinux for 8 d or duration of hospitalization.	2.5 mg s.c. daily	IA
SBC Brazilian guidelines 2015	Fondaparinux once a day for 8 d or until hospital discharge.	2.5 mg s.c. daily	IB

PCI: Percutaneous coronary intervention; UFH: Unfractionated heparin; NICE: National Institute for Health and Care Excellence; i.v.: Intravenous; s.c.: Subcutaneous.