Efficacy and Safety of Fondaparinux and Enoxaparin for Acute Coronary Syndromes in CKD

What did this Important Study Show? 

OASIS-5 was a multinational, randomized, double-blind, placebo-controlled, parallel-group study of fondaparinux versus enoxaparin in patients with unstable angina or non–ST-segment elevation myocardial infarction.11 Briefly, OASIS-5 compared the safety and effectiveness of enoxaparin, 1 mg/kg, subcutaneously every 12 hours with fondaparinux, 2.5 mg, subcutaneously once daily in 20,078 patients within 24 hours after the onset of unstable angina or non–ST-segment elevation myocardial infarction. In patients with a creatinine clearance (CCr) less than 30 mL/min, the enoxaparin dose was decreased to 1 mg/kg once daily; there were no dose adjustments for fondaparinux. Fondaparinux and enoxaparin could be administered for up to 8 days or until patient discharge. The primary objectives of the study were to: (1) show the noninferiority of fondaparinux compared with enoxaparin in the primary efficacy end point (death, myocardial infarction, or refractory ischemia) at 9 days; and (2) determine whether the safety profile of fondaparinux was superior to that of enoxaparin with respect to major bleeding. Patients were followed up for a minimum of 90 days and a maximum of 180 days.

The main results were reported in the April 6, 2006, edition of the New England Journal of Medicine.11 Fondaparinux and enoxaparin had similar composite cardiac event rates at 9, 30, and 180 days. However, fondaparinux had significantly lower bleeding rates at 9 days (2.2% versus 4.1%, respectively; hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.44 to 0.61; P < 0.001), 30 days (3.1% versus 5.0%, respectively; HR, 0.62; 95% CI, 0.54 to 0.72; P < 0.001), and 180 days (4.3% versus 5.8%, respectively; HR, 0.72; 95% CI, 0.64 to 0.82; P < 0.001). The investigators concluded that fondaparinux had efficacy similar to enoxaparin in decreasing the risk of cardiac ischemia at 9 days and had a significantly lower risk of bleeding.

In the September 4, 2007, edition of the Annals of Internal Medicine,12 this same investigative team published a subgroup analysis of these data to assess whether the increased bleeding risk noted with enoxaparin in OASIS-5 was related to the level of kidney function in study participants. Therefore, the efficacy and safety data from 19,979 OASIS-5 participants were stratified into quartiles based on estimated glomerular filtration rate ([eGFR]: <58 (N = 5,141); 58 to 71 (N = 4,845); 71 to 86 (N = 5012); and ≥86 mL/min/1.73 m2 (N = 4,996), respectively).

Regarding efficacy, fondaparinux had a significant benefit in decreasing the composite outcome of death, myocardial infarction, and refractory ischemia at day 30 only in patients with eGFR less than 58 mL/min/1.73 m2. All other eGFR groups had similar end point rates compared with enoxaparin. However, regarding safety, fondaparinux use was associated with significantly lower bleeding events compared with enoxaparin (Table 1). At day 9, fondaparinux use was associated with less major bleeding across all eGFR quartiles. This continued through days 30 and 180 for all eGFR quartiles with the exception of eGFR of 71 to 85 mL/min/1.73 m2. The most notable bleeding differences were found in those with an eGFR less than 58 mL/min/1.73 m2 (Table 1). At day 9, the HR for major bleeding events in the fondaparinux group was less than half that of the enoxaparin group (HR, 0.42; 95% CI, 0.32 to 0.56; P < 0.001) and continued to be significantly lower throughout the duration of the study (HR, 0.65; 95% CI, 0.52 to 0.80; P < 0.001 at 180 days).

Table 1. Efficacy and Safety Outcomes of Fondaparinux and Enoxaparin in the Subgroup Analysis of OASIS-5.

	Outcome	No. of Randomly Assigned Patients	Overall	Enoxaparin Group	Fondaparinux Group	Hazard Ratio (95% CI)	P
	Death, myocardial infarcation, or refractory ischemia
	9 d
	GFR < 58 mL/min/1.73 m2	5,141	363(7.1)	191(7.4)	172(6.7)	0.90(0.73-1.11)	0.32
	GFR 58-<71 mL/min/1.73 m2	4,845	297(6.1)	140(5.8)	157(6.4)	1.10(0.88-1.38)	0.41
	GFR 71-<86 mL/min/1.73 m2	5,012	235(4.7)	116(4.6)	119(4.8)	1.03(0.80-1.33)	0.81
	GFR ≥ 86 mL/min/1.73 m2	4,996	252(5.0)	123(4.9)	129(5.2)	1.05(0.82-1.34)	0.70
	Interaction	—	—	—	—	—	0.38
	30 d
	GFR < 58 mL/min/1.73 m2	5,141	573(11.1)	315(12.2)	258(10.0)	0.81(0.69-0.96)	0.01
	GFR 58-<71 mL/min/1.73 m2	4,845	409(8.4)	193(8.1)	216(8.8)	1.10(0.90-1.33)	0.34
	GFR 71-< 86 mL/min/1.73 m2	5,012	317(6.3)	163(6.5)	154(6.2)	0.95(0.76-1.18)	0.65
	GFR ≥ 86 mL/min/1.73 m2	4,996	361(7.2)	189(7.6)	172(6.9)	0.91(0.74-1.12)	0.37
	Interaction	—	—	—	—	—	0.45
	180 d
	GFR < 58 mL/min/1.73 m2	5,141	946(18.7)	495(19.6)	451(17.9)	0.90(0.79-1.03)	0.12
	GFR 58-<71 mL/min/1.73 m2	4,845	603(12.6)	297(12.6)	306(12.7)	1.01(0.86-1.19)	0.87
	GFR 71-< 86 mL/min/1.73 m2	5,012	467(9.4)	245(9.9)	222(9.0)	0.91(0.76-1.09)	0.30
	GFR ≥ 86 mL/min/1.73 m2	4,996	503(10.2)	265(10.7)	238(9.6)	0.90(0.75-1.07)	0.22
	Interaction	—	—	—	—	—	0.85
	Major bleeding events
	9 d
	GFR < 58 mL/min/1.73 m2	5,141	233(4.6)	163(6.4)	70(2.8)	0.42(0.32-0.56)	<0.001
	GFR 58-< 71 mL/min/1.73 m2	4,845	170(3.5)	110(4.6)	60(2.5)	0.53(0.39-0.72)	<0.001
	GFR 71-< 86 mL/min/1.73 m2	5,012	123(2.5)	74(3.0)	49(2.0)	0.66(0.46-0.95)	0.026
	GFR ≥ 86 mL/min/1.73 m2	4,996	103(2.1)	64(2.6)	39(1.6)	0.61(0.41-0.90)	0.014
	Interaction	—	—	—	—	—	0.056
	30 d
	GFR < 58 mL/min/1.73 m2	5,141	299(5.9)	193(7.6)	106(4.2)	0.54(0.42-0.68)	<0.001
	GFR 58-< 71 mL/min/1.73 m2	4,845	209(4.4)	127(5.4)	82(3.4)	0.62(0.47-0.82)	<0.001
	GFR 71-< 86 mL/min/1.73 m2	5,012	154(3.1)	88(3.5)	66(2.7)	0.75(0.55-1.03)	0.078
	GFR ≥ 86 mL/min/1.73 m2	4,996	145(2.9)	85(3.4)	60(2.4)	0.70(0.50-0.98)	0.036
	Interaction	—	—	—	—	—	0.093
	180 d
	GFR < 58 mL/min/1.73 m2	5,141	359(7.3)	216(8.7)	143(5.8)	0.65(0.52-0.80)	<0.001
	GFR 58-< 71 mL/min/1.73 m2	4,845	260(5.5)	147(6.3)	113(4.8)	0.74(0.58-0.95)	0.018
	GFR 71-< 86 mL/min/1.73 m2	5,012	191(3.9)	102(4.1)	89(3.6)	0.87(0.66-1.16)	0.350
	GFR ≥ 86 mL/min/1.73 m2	4,996	177(3.6)	103(4.2)	74(3.0)	0.71(0.53-0.96)	0.026
	Interaction	—	—	—	—	—	0.301

Note: Values expressed as number (percent) unless noted otherwise. Abbreviations: OASIS-5, Fifth Organization to Assess Strategies in Acute Ischemic Syndromes; CI, confidence interval; GFR, glomerular filtration rate. Adapted with permission from Fox et al.12

How does this Study Compare with Prior Studies? 

This is the first analysis specifically aimed at documenting the safety and efficacy of fondaparinux in patients with varying levels of kidney function; however, there have been analyses of enoxaparin in this population. A recent meta-analysis assessed the risk of bleeding and antifactor Xa levels in patients with stage 4 or non–dialysis-dependent stage 5 CKD treated with enoxaparin and other low-molecular-weight heparin preparations.3 In total, 18 clinical trials were analyzed; 8 focused solely on the use of therapeutic doses of enoxaparin (1 mg/kg every 12 hours or 1.5 mg/kg every 24 hours) in patients with a CCr of 30 mL/min or less,4, 13, 14, 15, 16, 17, 18, 19 whereas 4 studies focused on adjusted-dose enoxaparin administration in patients with a CCr of 30 mL/min or less.20, 21, 22, 23

Results of this meta-analysis showed 2 clinically significant findings: (1) a clear inverse relationship exists between CCr and peak antifactor Xa levels; and (2) the presence of a CCr of 30 mL/min or less was independently associated with increased risk of major bleeding events in patients receiving therapeutic-dose enoxaparin. For example, the odds ratio of severe bleeding in patients with a CCr of 30 mL/min or less receiving therapeutic enoxaparin dosing was nearly 4 times greater than that of patients with a greater CCr (odds ratio, 3.88; 95% CI, 1.78 to 8.45; P = 0.03). In the 4 studies that administered decreased doses of enoxaparin, there was no increase in adverse bleeding (odds ratio, 0.58; 95% CI, 0.09 to 3.78; P = 0.5). However, because the number of patients with a CCr less than 30 mL/min in these studies was small, these results should be interpreted with caution.

What Should Clinicians and Researchers Do? 

The OASIS-5 subgroup analysis provides encouraging clinical results. It suggests that fondaparinux has similar clinical efficacy and less major bleeding compared with enoxaparin, especially in patients with decreased kidney function. With respect to bleeding, this finding is surprising given that both drugs undergo extensive renal clearance and have prolonged plasma half-lives in patients with CKD. There are at least 2 potential explanations for this. First, unlike fondaparinux, which is excreted unchanged in urine, enoxaparin undergoes some hepatic metabolism into active and inactive heparin fragments that also are renally cleared. This prolongs its half-life in patients with CKD and may explain the increased bleeding. Second, the fondaparinux dose administered in the OASIS-5 trial (2.5 mg) is the lowest available dose and is less than the typical 5- to 10-mg doses generally administered for patients with deep vein thrombosis and pulmonary embolism. Therefore, one could argue that the patients in the OASIS-5 study received at least a 50% dose reduction compared with standard fondaparinux therapy. This may serendipitously be the most appropriate dose in patients with CKD.

These efficacy and safety data, although compelling, have some noteworthy limitations that preclude fondaparinux from becoming standard-of-care treatment for patients with ACS and PCI with CKD. First, the vast majority of subjects (approximately 75%) had eGFRs typically not considered clinically relevant when dosing drugs (ie, eGFR > 60 mL/min/1.73 m2). The lowest eGFR quartile classification was less than 58 mL/min/1.73 m2, and it was not clear how many of these patients truly had severe kidney disease (ie, eGFR < 30 mL/min/1.73 m2) versus moderate kidney disease (ie, eGFR, 30 to 59 mL/min/1.73 m2). It is possible that very few of these subjects had severe kidney disease; accordingly, it is unknown at this time how the efficacy and safety of fondaparinux would be influenced in patients with eGFR less than 30 mL/min/1.73 m2. This analysis would have benefited if the investigators described the baseline level of kidney function in the subject demographics and then classified them according to accepted CKD stages.

Second, subgroup analyses can be prone to produce misleading results, particularly when subgroups in the analysis are not defined a priori. The OASIS-5 study was neither designed nor powered a priori to determine the efficacy and safety of fondaparinux and enoxaparin in patients with varying levels of kidney function. Thus, these results should be considered exploratory and not confirmatory.

Third, at this time, fondaparinux is only FDA approved for the prophylaxis and treatment of patients with deep vein thrombosis and pulmonary embolism and is not approved for those with ACS. Because the practice of interventional cardiology has become highly evidence based and clinical practice guideline dominated, it is doubtful that cardiologists will routinely use non–FDA-approved drugs in highly complex procedures in high-risk patients, such as those with CKD.

Despite these limitations, this analysis touches on a key point that should be emphasized. Principally, to decrease the risk of bleeding, the therapeutic dose of enoxaparin should be decreased in patients with severe CKD. The FDA-approved package insert for enoxaparin suggests a dose decrease to 1 mg/kg subcutaneously once daily in patients with a CCr of 30 mL/min or less,24 whereas others suggested alternative dose adjustments.20, 21, 22, 23 The most appropriate dose decrease was not fully evaluated in the literature; therefore, at this time, it is prudent to follow the FDA-approved dosing guidelines and consider monitoring peak antifactor Xa levels to guide further dosing.

In conclusion, fondaparinux may be a safer alternative to enoxaparin in patients with decreased kidney function. These subgroup data provide a strong rationale for the development of additional large-scale analyses that assess the safety and efficacy of fondaparinux in patients with moderate to severe kidney disease.