The vascular access site for percutaneous coronary intervention (PCI) plays a central role among procedure-related risk factors for bleeding. The adoption of the transradial access (TRA) site as the first choice of vascular access in patients undergoing PCI has spread globally and has now been shown to reduce access site-related bleeding complications in an increasing number of populations and settings,1,2 such as elderly patients,3 and those presenting with acute coronary syndrome (ACS),4 renal failure,5 or cardiogenic shock.6 In patients with ACS, the reduced vascular and major bleeding complications of TRA is strongly associated with reduced mortality.7,8

It has been estimated that about 20% of patients with coronary artery disease undergoing PCI are at high risk of bleeding.9,10 This population is mostly composed of elderly patients (≥ 75 years), those taking chronic oral anticoagulation (OAC), and those with anemia, renal insufficiency or cancer, and/or requiring major surgery.10,11 While all bleeding avoidance strategies are of particular importance for such patients, there have been no studies specifically on the potential benefits and risks of TRA vs transfemoral access (TFA).

The current study represents a prespecified subanalysis of the LEADERS FREE trial,10,11 and aimed to assess the impact of TRA and TFA on bleeding complications and outcome at 30-days and 2-years of follow-up after PCI with either a polymer-free biolimus A9 drug-coated stent or a bare-metal stent10 in patients at high bleeding risk (HBR).

Among 2432 patients who underwent PCI in the LEADERS FREE trial, 1454 (59.8%) were treated ith TRA and 978 (40.2%) with TFA. Complete follow-up (excluding patients who withdrew from the study or were lost to follow-up) up to 730 days or death was achieved in 2387 (98.1%) patients (figure 1). A total of 325 patients (13.3% of the overall population) died during the study period. Cardiac death, which was part of the primary endpoint, occured in 156 (6.4%) of those patients and 169 (6.9%) were noncardiac. The breakdown of noncardiac death is given in the supplementary data (table 2 of the supplementary data and table 3 of the supplementary data). The choice of vascular access site varied considerably from center to center, and TRA use was ≥ 80% in 20/68 centers and ≤ 20% in 11/68.

Figure 1.

Study flowchart. BMS, bare-metal stent; DCS, drug-coated stent; PCI, percutaneous coronary interventions.

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The baseline characteristics and inclusion criteria are shown in table 1. Compared with TRA patients, TFA patients were more frequently female (27.9% vs 33.9%; P=.002) and had significantly more comorbidities. Most of baseline demographic and procedural characteristics were well matched for the 2 groups (table 1). As for trial inclusion criteria, the TRA group had more patients with planned surgery requiring interruption of dual antiplatelet therapy, and the TFA group had more patients with anemia and/or recent transfusion and more patients with renal failure. Compared with the TRA group, the TFA group had more patients with a left main target lesion, or a long target lesion, and also had a greater overall number of stents implanted, overlapping stents and total stent length per patient (table 2).

Primary endpoints

At 30 days, the primary safety endpoint (composite of cardiac death, myocardial infarction, or definite or probable stent thrombosis) had occurred in 43 patients (3.2%) in the TRA group and in 34 patients (3.4%) in the TFA group (hazard ratio [HR], 1.08; 95%CI, 0.68-1.70; P=.72) (table 3). The primary efficacy endpoint (clinically-driven target lesion revascularization) had occurred in 9 patients (0.7%) in the TRA and 5 patients (0.4%) in the TFA group (HR, 0.54; 95%CI, 0.15-1.91; P=.34) (table 3). The time-to-event curves for the primary safety and efficacy endpoints at 30 days are shown in figure 2.

Table 3.

Incidence of safety and efficacy endpoints at 30 days and 2 years

Endpoint	Radial (n=1454)	Femoral (n=978)	Hazard ratio (95%CI)	P
30-day outcome
Primary safety endpoint: cardiac death, myocardial infarction, or definite/probable stent thrombosis	43 (3.1)	34 (3.4)	1.08 (0.68-1.70)	.72
Cardiac death	14 (1.0)	8 (0.8)	0.82 (0.34-1.99)	.67
Myocardial infarction	33 (2.5)	23 (2.3)	0.89 (0.52-1.53)	.69
Definite or probable stent thrombosis	14 (1.0)	11 (1.0)	1.01 (0.45-2.26)	.98
Primary efficacy endpoint: clinically-driven TLR	9 (0.6)	5 (0.3)	0.54 (0.15-1.91)	.34
2-year outcome
Primary safety endpoint: cardiac death, myocardial infarction, or definite/probable stent thrombosis	188 (14.3)	139 (14.2)	1.00 (0.80-1.25)	.95
Cardiac death	89 (6.8)	67 (6.6)	0.98 (0.71-1.36)	.92
Myocardial infarction	119 (9.5)	88 (9.4)	0.99 (0.75-1.30)	.95
Definite or probable stent thrombosis	31 (2.3)	21 (2.3)	1.02 (0.59-1.76)	.93
Primary efficacy endpoint: clinically-driven TLR	119 (8.7)	94 (10.8)	1.24 (0.94-1.633)	.11

95%CI, 95% confidence interval; TLR, target lesion revascularization.

Unless otherwise specified, data are presented as No. (%).

Figure 2.

Time-to-event curves for the primary safety (A) and efficacy (B) endpoints at 2 years. 95CI%, 95% confidence interval; HR, hazard ratio.

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At 30 days, a major bleeding (BARC 3-5) had occurred in 78 patients: 29 (2.4%) in the TRA group and 49 (4.6%) in the TFA group (HR, 1.98; 95%CI, 1.25–3.11; P=.003). Among these, access site-related bleeding complications accounted for 20 (26%) patients, 4 in the TRA and 16 in the TFA (HR, 4.66; 95%CI, 1.59-13.69; P=.005) (figure 3). The remaining 58 (74%) major bleeding events were nonaccess site-related bleedings: 25 (2.1%) in the TRA group and 33 (3.2%) in the TFA group), and were mostly gastrointestinal bleedings in both groups (figure 3, figure 4, and table 4).

Figure 3.

Time-to-event curves for major bleeding (BARC 3-5) at 30 days (inset) and 2 years. 95CI%, 95% confidence interval; BARC, Bleeding Academic Research Consortium; HR, hazard ratio.

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Figure 4.

Time-to-event curves for access site (A) and nonaccess site (B) related major bleeding endpoints (BARC 3-5) at 30 days (inlet) and 2 years. 95CI%, 95% confidence interval; HR, hazard ratio.

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Table 4.

Incidence and location of major bleeding events (BARC 3-5) at 30 days and 2 years

Location	Radial (n=1454)	Femoral (n=978)	Hazard ratio (95%CI)	P
30-day outcome
All major bleedings	29 (2.3)	49 (4.6)	1.98 (1.25-3.11)	.003
Access site-related	4 (0.3)	16 (1.4)	4.66 (1.59-13.69)	.005
Nonaccess site-related	25 (2.0)	33 (3.1)	1.55 (0.92-2.59)	.09
Intracranial	1 (0.08)	3 (0.30)	4.28 (0.45-40.036)	.20
Gastrointestinal	16 (1.3)	14 (1.2)	0.91 (0.44-1.90)	.81
Retroperitoneal	1 (0.07)	3 (0.20)	4.07 (0.37-43.82)	.24
Pulmonary	0 (%)	1 (0.1)	N/A
Pericardial	1 (0.07)	0 (0)	N/A
Genitourinary	0 (0)	3 (0.3)	N/A
Intraspinal	0 (0)	0 (0)	N/A
Ocular	0 (0)	1 (0.1)	N/A
Nose	2 (0.1)	3 (0.2)	1.93 (0.27-13.51)	.50
Other	4 (0.3)	5 (0.5)	1.55 (0.44-5.48)	.49
2-year outcome
All major bleedings	101 (7.5)	109 (10.8)	1.51 (1.14-2.01)	.003
Access site-related	7 (0.5)	17 (1.5)	3.14 (1.27-7.76)	.01
Nonaccess site-related	94 (7.0)	93 (9.4)	1.39 (1.03-1.87)	.02
Intracranial	11 (0.7)	12 (1.4)	1.92 (0.82-4.52)	.13
Gastrointestinal	53 (4.0)	50 (4.9)	1.23 (0.82-1.84)	.29
Retroperitoneal	3 (0.2)	5 (0.4)	2.18 (0.50-9.48)	.29
Pulmonary	4 (0.2)	3 (0.3)	1.14 (0.23-5.69)	.86
Pericardial	1 (0.07)	0 (0)	N/A
Genitourinary	5 (0.3)	7 (0.7)	2.22 (0.66-7.41)	.19
Intraspinal	0 (0)	0 (0)	N/A
Ocular	3 (0.2)	2 (0.2)	0.99 (0.16-5.96)	.99
Nose	4 (0.4)	4 (0.3)	0.91 (0.23-3.52)	.89
Other	14 (1.0)	22 (2.4)	2.44 (1.24-4.83)	.009

95%CI, 95% confidence interval; N/A, not applicable

Data are presented as No. (%) or mean±standard deviation.

At 2 years, the primary safety endpoint had occurred in 327 (14.3%) patients: 188 (14.3%) in the TRA and 139 (14.3%) in the TFA (HR, 1.00; 95%CI, 0.80-1.25; P=.95) (table 3). The primary efficacy endpoint had occurred in 213 (9.6%) patients: 119 (8.8%) in the TRA group and 94 (10.9%) in the TFA group (HR, 1.24; 95%CI, 0.94-1.63; P=.11). The time-to-event curves for the primary safety and efficacy endpoints at 2 years are shown in figure 2.

At 2 years, a major bleeding had occurred in 101 patients (7.5%) in the TRA group and 109 patients (10.9%) in the TFA group (HR, 1.51; 95%CI, 1.14-2.01; P=.003). Among these, access site-related bleeding complications accounted for 24 (11%) patients, 7 in the TRA group and 17 in the TFA group (HR, 3.14; 95%CI, 1.27-7.76; P=.01). The remaining 187 (89%) major bleeding events were nonaccess site-related bleedings (94 [7.0%] for the TRA group and 93 [9.4%] for the TFA group; P=.02), and more than half were gastrointestinal bleedings in both groups (figure 3, figure 4, table 4). The associated mortality rate during the 2-year follow-up was similar for access- and nonaccess-related major bleeding events (figure 5). The results of the frailty model are provided in the supplementary data (table 4 of the supplementary data) and were in line with the standard analysis.

Figure 5.

Time-to-event curves for death at 2 years due to either access site- or nonaccess site-related bleeding. 95CI%, 95% confidence interval; HR, hazard ratio.

(0.18MB).

These data are the first to report on the impact of vascular access site on outcomes for HBR patients undergoing PCI. Two main findings emerged: a) the use of TRA was associated with a significantly reduced occurrence of major bleeding complications compared with TFA at 30 days and 2 years of follow-up, and was driven by a decrease in both access and nonaccess site bleeding; b) the safety and efficacy benefit of drug-coated stents over bare metal stents that have been previously reported11,12 are independent of vascular acces site, and are of similar magnitude following either radial or femoral access PCI.

The European Society of Cardiology guidelines for the management of ACS patients presenting with non–ST-segment elevation myocardial infarction recommends the use of TRA with a class I, level of evidence A, when it can be provided by experienced operators.13 Guidelines for the management of ST-segment elevation myocardial infarction patients recommend the use of TRA over TFA with a class IIa level of evidence B.14 In our study, including patients with ACS and stable coronary artery disease between 2012 and 2014, the use of TRA was 60%. This was perhaps less than could have been expected for an HBR population and reflects major variations between participating operators and centers: some centers used ≥ 80% TRA and other ≤ 20%. Patients treated with TFA tended to have more severe comorbidities, and while this may represent a clinically justified decision in some cases (contralateral internal mammary grafts are generally easier to cannulate using TFA, and arteriovenous shunts in the forearm of dialysis patients may contraindicate TRA), it could also represent a selection process by those less experienced operators who mostly use TRA for less comorbid patients and with favorable anatomy.

While access site-related bleeding is considered to comprise about half of all periprocedural bleeds in all-comer patients, the reported incidence of periprocedural bleeding complications varies greatly between trials, ranging from 1% to 12%, and is associated with a marked increase in 30-day mortality for ACS patients.15,16 The variation among trials is a function of the studied population as well as the definition used to classify bleeds.17,18 In our study, use of the radial route was associated with a significant decrease in the incidence of access site bleeding at 30 days and this benefit was maintained over the 2-year follow-up for HBR patients (figure 4A).

In a pooled patient-level analysis of 7 RCT,7 1-year mortality in patients with access site-related bleeding was significantly higher compared with patients without periprocedural bleeds (4.5% and 2.5%, respectively; OR, 2.03; 95%CI, 1.49-2.77). The mortality benefit associated with TRA vs TFA for ACS patients has also been confirmed by another meta-analysis19 and several mechanisms have been suggested to explain the association between bleeding events and mortality from ischemic causes; these include anemia, discontinuation of dual antiplatelet therapy, a prothrombotic state induced by bleeding, and the effects of blood transfusions.20 The fact that we observed no benefit of TRA vs TFA in terms of cardiac mortality, MI or ST in our trial, both at 30 days and at 2 years, may reflect several factors: only a minority of patients presented with ACS in LEADERS FREE, HBR patients may behave differently than all-comers, and the protocol-driven short dual antiplatelet therapy course for all patients could be expected to minimize the need for unplanned antiplatelet therapy adjustements beyond 30 days.

Importantly, HBR patients had an incidence of both access and nonaccess site bleeding events that was markedly higher than that observed for all-comer patients. At 30 days, we observed an overall major bleeding rate of 2.4% for the TRA group and 4.6% for the TFA group. In the RIVAL trial,1 which enrolled only ACS patients, non–CABG-related major bleeds at 30 days occurred in 0.7% of patients in the TRA group compared with 0.9% of patients in the TFA group. In the MATRIX trial,4 the overall incidence of major BARC 3 or 5 bleeding at 30 days was 1.6% in the radial group vs 2.3% in the femoral group. When considering long-term events in the present trial, 8.9% of patients had had a major bleeding event at 2 years, 7.5% in the TRA group and 10.9% in the TFA group. In the PARIS registry,21 which analyzed 4190 patients discharged after successful PCI with a guideline-based dual antiplatelet regimen, out-of-hospital major BARC 3 or 5 bleeding occurred in 3.3% over 2 years, but the choice of vascular access was not reported.

Nonaccess site-related major bleeding in our series accounted for more than three-quarters of all major bleeds in the TRA group and for more than two-thirds in the TFA group. This is more than the reported incidence in several other studies4,22 and clearly relates to the advanced age, high rate of comorbid conditions and need for OAC that define the HBR population studied in the LEADERS FREE trial. In a pooled analysis of 3 randomized clinical trials including more than 17 000 PCI patients,15 nonaccess site-related bleeding also represented the majority of all major and minor TIMI bleeding events, with a 4-fold increase in 1-year mortality, and the hazard ratio for 1-year mortality of a nonaccess site-related bleeding was approximately twice as high as that of access site bleed. The latter finding differs from the present series, in which the associated mortality rate during the 2-year follow-up was high and was similar for access- and nonaccess- related major bleeding events (HR, 0.83; 95%CI, 0.40-1.75, P=.63) (figure 5). This apparent discrepancy may be explained both by the definitions used for bleeding (TIMI vs BARC 3-5) and by the patient populations that were studied (all-comers vs HBR).

In our series, the location of major bleeding events was similar to previous reports of all-comer patients,15,23 with gastrointestinal, urinary, and intracranial events representing most nonaccess site-related major bleeding. The fact that nonaccess bleeding was significantly less frequent with TRA than TFA (table 4) most probably reflects the baseline inequalities between the 2 groups of patients rather than any specific benefit of TRA in this respect. Overall, the incidence of access-related bleeding between 30 days and 2 years was low in both groups, and all were associated with repeated invasive coronary, vascular or valvular procedures. Early studies reported an increased incidence of cerebrovascular embolization with TRA compared with TFA1. No impact of vascular access site was found in our population with respect to rates of stroke following PCI, and this is in line with a recently published meta-analysis.24

The use of TRA compared with TFA, was associated with a significantly reduced rate of both access site and nonaccess site major bleeding over a 2-year follow-up period after PCI in HBR patients, with similar outcomes in terms of clinically-driven target lesion revascularization and a composite safety endpoint including cardiac death, myocardial infarction, and stent thrombosis. The safety and efficacy benefits of drug-coated stents over drug-coated stent were independent of vascular access route.

LEADERS FREE trial was funded by Biosensors Europe.

P. Urban is a paid consultant to Biosensors, D. Walters has received research funding from Biosensors and both S. Copt and H.-P. Stoll are employees of Biosensors. None of the other coauthors have any conflict of interest to declare.