Cardiovasc Intervent Radiol DOI 10.1007/s00270-013-0577-3
CLINICAL INVESTIGATION
Clopidogrel Responsiveness in Patients Undergoing Peripheral Angioplasty Georgios Pastromas • Stavros Spiliopoulos • Konstantinos Katsanos • Athanasios Diamantopoulos • Panagiotis Kitrou • Dimitrios Karnabatidis Dimitrios Siablis
•
Received: 6 November 2012 / Accepted: 12 January 2013 Ó Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2013
Abstract Purpose To investigate the incidence and clinical significance of platelet responsiveness in patients receiving clopidogrel after peripheral angioplasty procedures. Materials and Methods This prospective study included patients receiving antiplatelet therapy with clopidogrel 75 mg after infrainguinal angioplasty or stenting and who presented to our department during routine follow-up. Clopidogrel responsiveness was tested using the VerifyNow P2Y12 Assay. Patients with residual platelet reactivity units (PRU) C 235 were considered as nonresponders (NR group NR), whereas patients with PRU \ 235 were considered as normal (responders [group R]). Primary end points were incidence of resistance to clopidogrel and target limb reintervention (TLR)-free survival, whereas secondary end
G. Pastromas (&) S. Spiliopoulos K. Katsanos A. Diamantopoulos P. Kitrou D. Karnabatidis D. Siablis Department of Interventional Radiology, Patras University Hospital, 26500 Patras, Greece e-mail:
[email protected] S. Spiliopoulos e-mail:
[email protected] K. Katsanos e-mail:
[email protected]
points included limb salvage rates and the identification of any independent predictors influencing clinical outcomes. Results In total, 113 consecutive patients (mean age 69 ± 8 years) with 139 limbs were enrolled. After clopidogrel responsiveness analysis, 61 patients (53.9 %) with 73 limbs (52.5 %) were assigned to group R and 52 patients (46.1 %) with 66 limbs (47.5 %) to group NR. Mean follow-up interval was 27.7 ± 22.9 months (range 3–95). Diabetes mellitus, critical limb ischemia, and renal disease were associated with clopidogrel resistance (Fisher’s exact test; p \ 0.05). According to Kaplan–Meier analysis, TLR-free survival was significantly superior in group R compared with group NR (20.7 vs. 1.9 %, respectively, at 7-year follow-up; p = 0.001), whereas resistance to clopidogrel was identified as the only independent predictor of decreased TLR-free survival (hazard rate 0.536, 95 % confidence interval 0.31–0.90; p = 0.01). Cumulative TLR rate was significantly increased in group NR compared with group R (71.2 % [52 of 73] vs. 31.8 % [21 of 66], respectively; p \ 0.001). Limb salvage was similar in both groups. Conclusion Clopidogrel resistance was related with significantly more repeat interventions after peripheral angioplasty procedures. Keywords Clopidogrel resistance Peripheral arterial disease Infrainguinal angioplasty Stenting
A. Diamantopoulos e-mail:
[email protected] P. Kitrou e-mail:
[email protected]
Introduction
D. Karnabatidis e-mail:
[email protected]
Clopidogrel, alone or in combination with aspirin, has been used for more than a decade as the key treatment in patients with peripheral arterial disease (PAD), especially after percutaneous endovascular procedures [1]. Clopidogrel is a
D. Siablis e-mail:
[email protected]
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thienopyridine antiplatelet agent that promotes patency and prevents the development of vascular restenosis or stent thrombosis after peripheral endovascular interventions by inhibiting platelet aggregation. Most of the supporting evidence is extrapolated from that related to the coronary circulation. Publication of the results of the CURE and PCI-CURE trials provided initial evidence of the efficacy of antiplatelet therapy in patients with acute coronary syndromes treated with percutaneous coronary intervention (PCI) [2, 3]. The combination of aspirin (75–325 mg daily) and clopidogrel (75 mg daily after a loading dose of 300 mg) has become the widely accepted regimen for stent-placement procedures. However, several additional studies have shown that a variable proportion of these patients have recurrent cardiovascular events and stent thrombosis after PCI despite receiving standard dual antiplatelet therapy [4, 5]. These events have been attributed to an inadequate antiplatelet drug effect or antiplatelet drug resistance (especially to clopidogrel) [6, 7]. Clopidogrel resistance is best defined as the lack of the desired pharmacologic effect of the drug. The exact clinical relevance of poor response to clopidogrel has been recently recognized and has increased the need for regular platelet-inhibition monitoring [8, 9]. The mechanism underlying the poor response to clopidogrel is still a matter of research and debate. Multiple factors have been proposed, including patient underdosing, decreased intestinal absorption, and alterations of the hepatic cytochrome P450 (CYP) system caused by interactions with other drugs, such as statins and certain proton pump inhibitors, as well as cytochrome P450 genetic polymorphisms [10–13]. However, evidence of the potential clinical consequences of clopidogrel resistance in patients with PAD after percutaneous management is missing. Furthermore, there is lack of data to confirm that individualized antiplatelet therapy may improve clinical outcomes after peripheral endovascular procedures; therefore, the routine observation of platelet inhibition is not widely used. The recently published MIRROR study, which investigated the efficiency of dual antiplatelet therapy, also described the incidence and stressed the clinical significance of nonresponsiveness to clopidogrel [14]. We herein present the long-term clinical outcomes of a prospective, single-centre study investigating the correlation of platelet responsiveness in patients receiving clopidogrel with the rate of repeat procedures after percutaneous endovascular treatment of infrainguinal PAD.
included all patients who received daily antiplatelet therapy with clopidogrel, 75 mg po, after peripheral percutaneous transluminal angioplasty (PTA) or stenting and returning to our department for regular clinical follow-up or because of clinical relapse of PAD between February 2011 and August 2012. The study included patients receiving regular, daily clopidogrel (75 mg) therapy after previous infrainguinal angioplasty or stenting procedure of the femoropopliteal axis, the infrapopliteal vessels, or both in our department due to either intermittent claudication (IC) or critical limb ischemia (CLI). Patients not receiving clopidogrel regularly were excluded from the study. Inclusion and exclusion criteria are listed in Table 1. Clopidogrel responsiveness was tested using the VerifyNow P2Y12 Assay (Accumetrics, CA) after peripheral blood sampling according to the company’s official guiding principles [15]. All patients fulfilling the study’s criteria signed an inform consent before blood sampling. In all patients, peripheral blood sampling to evaluate platelet response to clopidogrel was performed after at least 3 months of clopidogrel intake after the procedure and receiving continued clopidogrel therapy. Patient selection was performed using nonprobability consecutive sampling technique. Currently there are no data to indicate the optimal cut-off value of platelet inhibition to predict clinical outcomes of peripheral endovascular procedures. According to published coronary studies assessing platelet reactivity using the VerifyNow assay, the established optimal cut-off value after PCI ranges from 230 to 240 platelet reactivity units (PRUs). Therefore, in this study patients with residual PRU C 235 were considered low responders or nonresponders and were included in group NR, whereas patients with PRU \ 235 were considered responders and were included in group R [16, 17]. The term ‘‘clopidogrel resistance’’ herein describes both low responsivenenss and nonresponsiveness to the drug. The study’s primary end point included the comparison of target limb reintervention (TLR)-free survival rates between the two study arms, the incidence of nonresponders to clopidogrel, and the identification of any independent predictors influencing TLR-free survival. TLR was defined as the absence of any additional clinically driven recanalization procedure of the target limb because of symptom relapse. Secondary end points included amputation-free survival and minor complication rates. Patients’ baseline demographics, procedural details, imaging, and clinical followup were recorded in our department’s electronic database and in the patients’ personal medical files. Statistical Analysis
Materials and Methods The study was approved by the hospital’s Ethical and Scientific Committee. This was a prospective audit that
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Discrete variables were presented as counts and percentages and continuous variables as medians and interquartile ranges (i.e., between the 25 and 75th percentiles) in
G. Pastromas et al.: Clopidogrel Responsiveness in Peripheral Procedures Table 1 Inclusion and exclusion criteria Inclusion criteria Patients on regular daily POS clopidogrel, 75 mg, and previous peripheral balloon angioplasty or stenting procedure Severe IC or CLI Femoropopliteal or infrapopliteal procedures or both Exclusion criteria Uncertainty regarding regular intake of clopidogrel, 75 mg daily, after endovascular procedure Solely aortoiliac endovascular procedures Endovascular treatment of acute limb ischemia Systemic coagulopathy or hypercoagulation disorders
parentheses or as mean ± SD if they assumed a normal distribution. Kolmogorov–Smirnov goodness-of-fit test was applied to define whether continuous data were originating from normal distributions, and Student t test was used to determine the significance of difference in case the variables passed the normality test. In cases in which the continuous variables did not pass the normality test, Mann– Whitney test was applied. A comparison between two proportions was performed by challenging the null hypothesis that these proportions were equal using a standardized normal deviate test. Fisher’s exact test was used to calculate the association between variable predictive factors (diabetes mellitus [DM], chronic renal disease [RD], PPI, statins, acetylsalicylic acid, cardiac disease, CLI, arterial hypertension, and smoking) and clopidogrel resistance. Kaplan–Meier bivariable statistical analysis was employed for calculation of TLR-free survival between the two study arms, whereas Kaplan–Meier curves were compared using log-rank test. Results were stratified according to platelet inhibition (group NR vs. group R). Stepwise regression analysis was performed with Cox multivariable proportional-hazards regression analysis to identify any independent predictors affecting TLR-free survival. Dependent variables included DM, RD (increased serum creatinine level [1.5 mg/dL), smoking habit within the past 24 months, regular statin use, protein pump inhibitors (PPI) or acetylsalicylic acid intake, target lesion location (femoropopliteal or infrapopliteal), treatment modality (balloon angioplasty or stenting), and platelet inhibition status (R vs. NR). The covariate was TLR-free survival. Multivariable analysis results were presented as hazard ratios (HRs) with 95 % confidence intervals (CIs) and the associated level of statistical significance (p). Adjusted Cox curve plots were presented only in cases of statistically significant results. Statistical analysis was performed using the SPSS/PASW statistical software package (version 20.0; SPSS/PASW, Chicago, IL), and statistical significance was set at 0.05.
Results In total, 113 patients (95 male [84 %]), mean age 69 ± 8 years, were enrolled in the study. Overall, 139 limbs previously treated with PTA or stenting were analysed. The majority of the patients had CLI (66 of 113 [58.4 %]) and DM (64 of 113 [56.6 %]); 17 of 113 patients (19.2 %) were receiving dialysis due to chronic renal failure; and 81 of 113 patients (71.7 %) were receiving statin therapy. Treated lesions were mainly located in the femoropopliteal axis (82 of 139 [72.5 %]), whereas in 48 of 139 limbs (34.5 %) both femoropopliteal and infrapopliteal lesions and in 9 of 139 lesions (6.5 %) only infrapopliteal lesions were treated. As a result, in a total of 130 femoropopliteal lesions (56 of 130 [43.1 %] balloon angioplasty and 74 of 130 [56.9 %] stenting) and 59 infrapopliteal (57 of 59 [96.6 % stenting]) endovascular procedures were analysed. All stents used in the femoropopliteal axis were bare, selfexpandable nitinol stents, whereas stents used in the infrapopliteal lesions were balloon-expandable sirolimusor everolimus-eluting stents. At the end of the procedure, in all limbs (100 %) at least one runoff vessel patent to the distal foot was shown on angiography. According to the clopidogrel responsiveness analysis, 61 of 113 patients (53.9 %) with 73 of 113 limbs (52.5 %) showed insufficient platelet inhibition (C235 PRU) and were defined as nonresponders (group NR), whereas 52 of 113 patients (46.1 %) with 66 of 113 limbs (47.5 %) showed sufficient platelet inhibition (\235 PRU) and were defined as responders (group R). Significantly more patients with CLI (43 [70.5 %] vs. 23 [44.2 %]; p = 0.007], DM (2 of 61 [68.9 %] vs. 22 of 52 [42.3 %]; p = 0.007), and chronic renal failure (13 of 61 [21.3 %] vs. 3 of 52 [7.7 %]; p = 0.03) were included in group NR compared with group R, respectively (Fig. 1). All patients included in this study received dual antiplatelet therapy with clopidogrel, 75 mg 1 9 1, and acetylsalicylic acid, 100 mg 1 9 1, for the first 6 months after the procedure and continued with clopidogrel monotherapy. Mean time follow-up was 27.7 ± 22.9 months (range 3–95), whereas there was no significant difference in mean follow-up time between the two study arms (26.7 ± 20.2 months for group R vs. 28.5 ± 24.8 months for group NR, p = 0.80). Patients’ baseline demographics stratified according to the two study arms are listed in Table 2. Analysis of the angiographic images showed that in all TLR procedures (73 of 73 [100 %]), at least one previously treated target lesion was retreated. Cumulative TLR rate was significantly greater in NR compared with group R (71.2 % [52 of 73] vs. 31.8 % [21 of 66], respectively; p \ 0.001). According to bivariable Kaplan–Meier statistical analysis, estimated TLR-free survival at B7 years follow-up was significantly superior in group R compared
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G. Pastromas et al.: Clopidogrel Responsiveness in Peripheral Procedures Table 2 Baseline patient demographics and clinical status stratified according to study group Demographics
Group R
Group NR
p
Patients (n)
52
61
– –
Limbs (n)
66
73
Male sex
46 (88.5)
49 (80.3)
0.30
Age (years)
67.3 ± 9.2
71.6 ± 8.1
0.12
Smoking habit
36 (69.2)
34 (55.7)
0.17
DM
22 (42.3)
42 (68.9)
0.007
Arterial hypertension Chronic renal failure
43 (82.6) 4 (7.7)
54 (88.5) 13 (21.3)
0.42 0.03
Cardiac diseasea
13 (25.0)
21 (34.4)
0.30
PPI use
15 (28.8)
17 (27.7)
0.68
Statin use
33 (63.5)
43 (70.5)
0.54
Acetylsalicylic acid use
49 (94.2)
54 (88.5)
0.33
3
29 (55.8)
18 (29.5)
0.007
4
15 (28.8)
27 (44.3)
0.11
5
8 (15.4)
13 (21.4)
0.47
6
0 (0)
3 (4.9)
0.24
CLI
23 (44.2)
43 (70.5)
0.007
Rutherford stage of PAD Fig. 1 Factors correlated with resistance to clopidogrel. Histogram showing the distribution of the main demographic factors between groups R and NR with the corresponding level of statistical significance. According to Fisher exact test, DM, CLI, and chronic RD were associated with resistance to clopidogrel
with group NR (98.1 vs. 87.0 %, 55.6 vs. 44.9 %, 41.4 vs. 23.4 %, and 20.7 vs. 1.9 % in group R vs. group NR at 1, 3, 5, and 7 years, respectively, p = 0.001 log-rank test; Fig. 2). Numbers of subjects at risk in group R were 52, 15, 8, and 2 and in group NR were 50, 24, 14, and 2 at 1, 3, 5 and 7 years, respectively. Interestingly, after adjustment for confounding factors of heterogeneity using Cox multivariable regression analysis, resistance to clopidogrel was identified as the only independent predictor for decreased TLR-free survival (HR 0.536, 95 % CI 0.31–0.90; p = 0.01; Fig. 3). Kaplan–Meier analysis estimated a comparable limb salvage rate between the two study arms after B7 years of follow-up (98.3 % in group R vs. 96.7 % in group NR, p = 0.56 log-rank test) (Fig. 4), whereas cumulative minor amputation rates were similar in both groups (1 of 66 [1.5 %] in group R vs. 2 of 73 [2.7 %] group NR, respectively; p = 0.30). Procedural details and study outcomes are listed in Table 3.
Continuous data are presented as means ± SDs and categorical data given as counts with percentages in parentheses PPI proton pump inhibitors, PAD peripheral arterial disease, CLI critical limb Ischemia a
History of myocardial infarction (MI) or occult MI by electrocardiogram (ECG), stable or unstable angina, arrhythmia, and congestive heart failure
Discussion Although antiplatelet therapy with clopidogrel is recommended after peripheral endovascular procedures, data regarding the optimal postprocedural antiplatelet therapy are scarce, whereas the incidence and clinical significance of the phenomenon of resistance to clopidogrel in PAD patients remains ‘‘terra incognita.’’ As a result, until today there are no clear guidelines indicating the proper antiplatelet regime after endovascular management of PAD [1, 18–21]. The term ‘‘clopidogrel resistance’’ is widely
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Fig. 2 Kaplan–Meier TLR-free survival plots
G. Pastromas et al.: Clopidogrel Responsiveness in Peripheral Procedures Table 3 Procedural details and outcomes Details and outcomes
Group R
Group NR
p
Femoropopliteal procedures
60
70
–
Infrapopliteal procedures
29
30
–
Stent use (%) Femoropopliteal
33/59 (55.9)
41/71 (57.7)
0.41
Infrapopliteal
29/29 (100)
28/30 (93.3)
0.07
Runoffb Amputation-free survival (%)a
66/66 (100) 98.3
73/73 (100) 96.7
1 0.56
Minor amputations
1/66 (1.5)
2/73 (2.7)
0.30
Cumulative TLR
52/73 (71.2)
21/66 (31.8)
0.001
Categorical data are given as counts and percentages in the parentheses
Fig. 3 TLR-free survival Cox adjusted plot stratified for group R versus group NR
Fig. 4 Kaplan–Meier limb salvage plots for groups R and NR
used to describe the failure of conventional clopidogrel dosing to achieve its antiaggregatory effect, and it has been associated with increased rates of major adverse cardiovascular events after PCIs [7, 22]. Although the relation of this phenomenon with adverse cardiac events has been widely documented in coronary studies, there are currently no data regarding its clinical significance in the ambit of PAD [23]. Only recently, Tepe et al. reported the first short-term outcomes from a prospective, randomized,
a
Up to 7 years of follow-up
b
At least one patent infrapopliteal vessel to the distal foot
double-blind trial investigating the clinical effectiveness of dual antiplatelet therapy with clopidogrel, 75 mg, and acetylsalicylic acid, 100 mg, versus monotherapy with acetylsalicylic acid, 100 mg. In total, 80 patients were randomized into the two study arms, and significantly fewer reinterventions were noted in the clopidogrel group at 6-month follow-up (2 of 40 [5 %] vs. 8 of 40 [20 %]; p = 0.04) [14]. Interestingly, this was also the first trial to report the incidence of low responsiveness or nonresponsiveness to clopidogrel in patients undergoing peripheral endovascular treatment due to severe IC or CLI and was detected in 30 % of cases. This rate was similar to that previously reported from coronary studies in which 4–30 % of patients treated with standard clopidogrel doses did not demonstrate sufficient antiplatelet response [22]. In this study, the incidence of clopidogrel resistance was 53 %, similar to that reported in patients with atherosclerotic cerebrovascular disease [24, 25]. The investigators speculate that the discrepancy between the MIRROR trial and the herein reported resistance rate could be attributed to the greater rate of statin use, DM, and RD compared with the MIRROR trial (71.7 vs. 62.5 %, 56.6 vs. 37.5 %, and 19.2 vs. 0 %, respectively) because these factors have been previously associated with increased nonresponsiveness to clopidogrel [26, 27]. In fact, in this study DM and RD were associated with decreased response to clopidogrel. Moreover, a greater fraction of CLI patients was investigated (66 of 113 [58.4 %]) compared with the MIRROR trial (27 of 80 [33.7 %]). According to our results, CLI was also correlated to clopidogrel resistance, thus signifying a possible association between PAD and increased platelet reactivity. The study’s results showed a greater rate of CLI, DM, and RD between NRs in the patient cohort. The mechanism behind poor responsiveness to clopidogrel appears to be multifactorial and controversial. Increased platelet turnover in DM patients, [26] and
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decreased absorption of the drug in patients with increased GFR [27] may contribute to clopidogrel hyporesponsiveness. The investigators also suggest that the wide variety of drugs coadministrated to these patients may lead to interaction between drugs that compete for the same metabolic pathway and consequently affect clopidogrel activation in the hepatic cytochrome CYP system. Nevertheless, further investigation is needed to evaluate the effectiveness of such an approach. The study’s primary end point was confirmed by both bivariable Kaplan–Meier and multivariable Cox regression analysis. According to log-rank test, patients in group R showed a significantly superior long-term TLR-free survival rate at B7 years of follow-up after femoropopliteal and infrapopliteal angioplasty or stenting procedures, whereas clopidogrel resistance was identified as the only independent predictor for decreased TLR-free survival rate because patients in group NR had an almost 2-fold increased risk of a repeat procedure (HR 0.536). This study’s population was characterized by an increased mean age of nearly 70 years. However, according to Cox multivariable analysis, age was not detected as an independent predictor of decreased TLR-free survival, probably because the majority of the patients were of a similar age. In addition, the multivariable analysis model did not detect any other independent predictor influencing primary outcome, indicating that factors, such as the use of stent or balloon angioplasty, CLI, smoking habit, DM, and RD, did not significantly affect clinical outcomes compared with the response to antiplatelet therapy. These results are in accordance with the short-term outcomes of the MIRROR study, in which the only two patients who underwent TLR in the dual antiplatelet therapy group were NRs [14]. To the best of our knowledge, this is the first study to report the clinical significance of inadequate platelet responsiveness to clopidogrel after infrainguinal angioplasty or stenting. Subsequent to these results, the investigators recommended regular clopidogrel responsiveness testing for all patients receiving clopidogrel therapy after endovascular procedures for the management of PAD. Because trials investigating novel antiplatelet therapy protocols after peripheral angioplasty are missing, in our department case-sensitive alternative antiplatelet therapy is administrated in patients with resistance to clopidogrel consistent with current coronary guidelines [21, 28]. The recognized clinical impact of resistance to clopidogrel in the field of coronary disease has motivated several investigators to investigate alternative antiplatelet therapeutic regimes in cases of documented clopidogrel resistance, including clopidogrel dosage modifications and the use of novel antiplatelet agents, such as prasugrel and ticagrelor [28–32]. Accordingly, in our department, a double clopidogrel dose (150 mg daily) was prescribed in NRs. In cases of failure to improve platelet inhibition
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reaching a value\235, aspirin, 100 mg daily, or ticagrelor, 90 mg twice a day, was prescribed on an individual patient basis. However, the investigators recognize that this is not evidence-based and that currently RCTs are missing to confirm whether this is the best medical practice in the peripheral arteries. Among the limitations of this study are the relatively small number of patients investigated and the single-centre observational design, which might generate an inherent bias. Moreover, this study was not designed to analyse angiographic end points, such as target lesion binary restenosis rate and its possible correlation with high platelet reactivity after clopidogrel therapy, and thus lacks a credible control arm. In conclusion, in the era of continuously developing minimal invasive technology where sophisticated endovascular devices, such as drug-eluting stents and drugcoated balloons, are currently endorsed in the majority of current therapeutic protocols, clopidogrel resistance may represent a crucial independent factor negatively influencing short-, mid-, and long-term clinical outcomes. We found that clopidogrel resistance was the only independent predictor for decreased TLR-free survival after long-term follow-up. CLI, DM, and chronic RD were all associated with resistance to clopidogrel. Large-scale, well-designed trials are of the utmost importance to provide critical scientific evidence regarding the incidence and clinical significance of the phenomenon of clopidogrel resistance after peripheral endovascular procedures. Conflict of interest of interest.
The authors declare that they have no conflict
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