From the Midwestern Vascular Surgical Society
Cilostazol and freedom from amputation after lower extremity revascularization J. David Neel, MD,a Robin L. Kruse, PhD,b Viktor Y. Dombrovskiy, MD, PhD, MPH,c and Todd R. Vogel, MD, MPH,a Columbia, Mo; and New Brunswick, NJ Objective: Cilostazol, an antiplatelet agent with vasodilating properties, has not been well evaluated in conjunction lower extremity revascularization (LER). We evaluated the association between cilostazol and limb salvage after endovascular or open surgery for LER. Methods: Patients aged $65 years undergoing LER were identified from 2007 to 2008 Medicare Provider Analysis and Review and Carrier files using International Classification of Diseases-9 Edition-Clinical Modification and Current Procedural Terminology-4 codes. Covariates included demographics, comorbidities, and disease severity. Use of cilostazol was identified using National Drug Codes and Part D files. Outcomes were compared using c2 and Kaplan-Meier analyses and Cox regression. Results: We identified 22,954 patients undergoing LER: 8128 (35.4%) with claudication, 3056 (13.3%) with rest pain, and 11,770 (51.3%) with ulceration/gangrene. Among them, 1999 patients (8.7%) used cilostazol before LER. More patients received endovascular (14,353) than open (8601) procedures. Cilostazol users had fewer amputations than nonusers at 30 days (7.8% vs 13.4%), 90 days (10.7% vs 18.0%), and 1 year (14.8% vs 24.0%; P < .0001 for all). Cox proportional hazards regression with adjustment for age, gender, race, comorbidities, type of procedure, and atherosclerosis severity showed noncilostazol users were more likely to undergo amputation #1 year after surgery (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.02-1.29; P [ .02). Subgroup analyses using Cox proportional hazards models adjusted for age, gender, and comorbidities demonstrated significantly improved 1-year amputation-free survival for patients with renal failure (HR, 1.61; 95% CI, 1.28-2.02; P < .001) and diabetes (HR, 1.61; 95% CI, 1.36-1.92; P < .001) who were taking cilostazol. Conclusions: In patients undergoing LER, cilostazol use was associated with improved 1-year freedom from amputation. Patients with renal failure and diabetes also demonstrated a significant benefit from taking cilostazol. Further studies are needed to evaluate the benefits of cilostazol after LER. (J Vasc Surg 2015;-:1-5.)
Peripheral arterial disease (PAD) is a relatively common disease affecting the lives of millions of Americans, particularly men and women aged >40 years.1,2 Among patients with symptoms of claudication, the amputation rate is w1% to 3% in 5 years; however, overall mortality in this cohort of patients approaches 40% at 5 years.1 Cilostazol, an oral phosphodiesterase-3 inhibitor, is frequently used to treat patients with symptomatic claudication. Its effects are believed to be mediated by its vasodilatory properties as well as an inhibitory effect on platelet aggregation.3,4 In addition, newer studies suggest cilostazol may play a role in decreasing intimal hyperplasia after angioplasty and stenting in coronary vessels.5-7 From the Division of Vascular Surgery, Department of Surgerya and Department of Family and Community Medicine,b University of Missouri School of Medicine, Columbia; and the Department of Surgery, Rutgers-Robert Wood Johnson Medical School, New Brunswick.c Author conflict of interest: none. Presented at the Plenary Session of the Thirty-eighth Annual Meeting of the Midwestern Vascular Surgical Society, Coralville, Iowa, September 4-6, 2014. Reprint requests: Todd R. Vogel, MD, MPH, Department of Surgery, Division of Vascular Surgery, University of Missouri Hospital & Clinics, One Hospital Dr, Columbia, MO 65212 (e-mail: vogeltr@health. missouri.edu). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214 Copyright Ó 2015 by the Society for Vascular Surgery. http://dx.doi.org/10.1016/j.jvs.2014.11.067
In patients with PAD undergoing a lower extremity revascularization (LER) procedure, the goal of therapy is to prevent limb loss. This analysis evaluated the association between cilostazol use in the Medicare population and outcomes after LER procedures, including endovascular and open procedures for LER. METHODS This study was approved by the Institutional Review Boards at the University of Missouri School of Medicine and the Rutgers-Robert Wood Johnson Medical School. Informed patient consent was not needed because the Medicare data were deidentified. Data source. Data for this analysis were captured from the following Centers for Medicare & Medicaid Services files for the years 2007 to 2008: Medicare Provider Analysis and Review (MedPAR), Carrier Claim File, Part D Drug Event (PDE), and the Beneficiary Summary File. MedPAR data contain information for Medicare hospitalized patients, such as sociodemographic characteristics, diagnoses, procedures provided during the hospitalization, hospital length of stay, various charges, and patient outcomes at discharge. The Carrier Claim file provides information about surgical procedures using the Current Procedural Terminology 4 (CPT-4) procedure codes, which are more specific and detailed than the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) procedure codes. The PDE File, using 1
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2 Neel et al
the National Drug Codes (NDC), provides data on prescription drugs dispensed to Medicare beneficiaries. The Beneficiary Summary File covers Medicare enrollment, including Part D. The unique personal identifier for each Medicare beneficiary is the same in the different files, allowing linkage between these files. Study population. The analysis included Medicare beneficiaries aged $65 years who were electively hospitalized with a diagnosis of atherosclerosis of LE arteries for LER in 2007 to 2008 and had Part D coverage. From the Beneficiary Summary File, we selected individuals with enrollment in Medicare Part D for the entire calendar year. Then, using the MedPAR data, we selected from this cohort those who were hospitalized with a diagnosis of intermittent claudication (ICD-9-CM diagnosis code 440.21), rest pain (440.22), ulceration (440.23), or gangrene (440.24). Finally, using the Carrier File, we included in the study cohort only those patients who underwent LER by endovascular procedure (CPT-4 codes 35470, 35473, and 35474) or open surgery (35556, 35583, 35656 [femoral-popliteal bypass]; 35566, 35585, 35666 [femoral-tibial bypass]). Cilostazol use was identified with the following NDC codes in the Part D Drug Event File: 00054002821, 00185012305, 00185012360, 00185022305, 00185022360, 16590028530, 16590028560, 16590028590, 54868541100, 54868541101, 59148000216, 59148000316, 60429076260, 60429076305, 60429076360, 63629464401, 63629464402, 63629511201, 63629511202, 63629511203, 63629511204, 64720015806, 64720015906, and 64720015950. LE amputations were recognized with the CPT-4 codes 27590, 27591, 27592, 27880, 27881, 27882, 28800, 28805, 28810, 28820, and 28825. ICD-9-CM diagnosis codes for secondary diagnoses were used to identify postoperative complications: 997.1, 410.00-410.02, 410.10-410.12, 410.20-410.22, 410.30-410.32, 410.40410.42, 410.50-410.52, 410.60-410.62, 410.70-410.72, 410.80-410.82, 410.90-410.92, and 427.5 for cardiac complications, including myocardial infarction; 997.3x, 480.x, 481, 482.0-482.2, 482.3x, 482.4x, 482.8x, 482.9, 483.x, 484.x, 485, 486, 507.0, 512.1, 518.4, 518.5, 518.81, and 518.82 for respiratory complications and pneumonia; 997.5, 584.x, and 593.81 for renal complications and acute renal failure; 996.62, 998.30-998.32, 998.5x., and 999.3x for surgical infection; 998.11 for hemorrhage and 998.12 for hematoma complicating LER. Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project comorbidity software measures were used to evaluate comorbidities in the study population (available at http://www.hcup-us.ahrq.gov/ toolssoftware/comorbidity/comorbidity.jsp#download). We included in the analysis the following comorbid conditions: congestive heart failure, chronic pulmonary disease, pulmonary circulation disease, hypertension, diabetes, renal failure, and obesity. Statistical analysis. All analysis were performed with SAS 9.3 software (SAS Institute Inc, Cary, NC). The Student t-test was used to evaluate differences between
continuous variables. Differences between categoric variables were analyzed by c2 Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. We also computed 30-day, 90-day, and 1-year crude amputation rates. To take into account potential confounders while comparing these rates between study groups, we used stepwise multivariable logistic regression analysis with adjustment for age, gender, race, severity of disease (claudication, rest pain, or ulceration/gangrene), comorbidities, type of procedure (endovascular or open surgery), and cilostazol use. The 1-year freedom from amputation was analyzed with Kaplan-Meier survival curves and Cox proportional hazards regression, with adjustment by the same covariates as in the logistic regression models. We selected 789 patients (3.4%) who received cilostazol only after the procedure and compared them with patients who received cilostazol before the procedure (including those who continued taking medication after procedure) and patients who did not take cilostazol. P # .05 was considered statistically significant. RESULTS A total of 22,954 patients were selected for analysis: 1999 were prescribed cilostazol preoperatively and 20,955 were not. Among patients who received cilostazol before LER, 44.3% continued to receive it after the procedure. This proportion was approximately the same in patients with claudication (44.7%), rest pain (46.7%), and ulceration/gangrene (42.9%). Table I reports the characteristics of both groups. Although we found statistically significant differences in the mean age of patients between the two groups, this difference was not clinically important. Gender distribution in both groups was similar. Compared with those not taking cilostazol, the proportion of African Americans in the cilostazol group was smaller, and the proportion of Hispanics was greater. Patients with cilostazol had greater rates of hypertension and chronic pulmonary disease, whereas their counterparts experienced more renal failure. Approximately one-third of patients without preoperative cilostazol experienced claudication, and more than half had ulceration or gangrene. Conversely, almost half of patients in the group taking cilostazol had claudication compared with one-third who experienced ulceration or gangrene. In both groups, endovascular repairs predominated over open surgery. Patients who received cilostazol before LER compared with those without cilostazol demonstrated lower crude amputation rates at 30 days (7.8% vs 13.4%), 90 days (10.7% vs 18.0%), and 1 year (14.8% vs 24.0%; P < .0001 for all) after both endovascular repairs (Fig 1, A) and open surgery (Fig 1, B). In multivariable logistic regression analysis, however, we found a significant association of preoperative cilostazol use on amputation rates at 1 year postprocedure. Patients without cilostazol were more likely to undergo amputation during the year after the index procedure than those with cilostazol (OR, 1.19; 95% CI, 1.02-1.37; P ¼ .02). Patients receiving cilostazol after the procedure had no significant difference
JOURNAL OF VASCULAR SURGERY Volume -, Number -
Neel et al 3
Table I. Characteristics of the study population Treatment
Characteristicsa Age, years Age groups, years 65-69 70-74 75-79 $80 Gender Male Female Race/ethnicity White African American Hispanic Other and unknown Comorbidities Hypertension Chronic pulmonary disease Pulmonary circulation disease Diabetes Renal failure Obesity Atherosclerosis severity Claudication Rest pain Ulceration/gangrene Procedure Endovascular Open surgery
Without cilostazol (n ¼ 20,955)
With cilostazol (n ¼ 1999)
P
76.0 6 7.8
75.5 6 7.1
.006
5437 4370 4117 7031
(26.0) (20.8) (19.6) (33.6)
505 450 457 587
(25.3) .51 (22.5) .08 (22.9) .0006 (29.3)
Cilostazol and freedom from amputation after lower extremity revascularization J. David Neel, MD,a Robin L. Kruse, PhD,b Viktor Y. Dombrovskiy, MD, PhD, MPH,c and Todd R. Vogel, MD, MPH,a Columbia, Mo; and New Brunswick, NJ Objective: Cilostazol, an antiplatelet agent with vasodilating properties, has not been well evaluated in conjunction lower extremity revascularization (LER). We evaluated the association between cilostazol and limb salvage after endovascular or open surgery for LER. Methods: Patients aged $65 years undergoing LER were identified from 2007 to 2008 Medicare Provider Analysis and Review and Carrier files using International Classification of Diseases-9 Edition-Clinical Modification and Current Procedural Terminology-4 codes. Covariates included demographics, comorbidities, and disease severity. Use of cilostazol was identified using National Drug Codes and Part D files. Outcomes were compared using c2 and Kaplan-Meier analyses and Cox regression. Results: We identified 22,954 patients undergoing LER: 8128 (35.4%) with claudication, 3056 (13.3%) with rest pain, and 11,770 (51.3%) with ulceration/gangrene. Among them, 1999 patients (8.7%) used cilostazol before LER. More patients received endovascular (14,353) than open (8601) procedures. Cilostazol users had fewer amputations than nonusers at 30 days (7.8% vs 13.4%), 90 days (10.7% vs 18.0%), and 1 year (14.8% vs 24.0%; P < .0001 for all). Cox proportional hazards regression with adjustment for age, gender, race, comorbidities, type of procedure, and atherosclerosis severity showed noncilostazol users were more likely to undergo amputation #1 year after surgery (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.02-1.29; P [ .02). Subgroup analyses using Cox proportional hazards models adjusted for age, gender, and comorbidities demonstrated significantly improved 1-year amputation-free survival for patients with renal failure (HR, 1.61; 95% CI, 1.28-2.02; P < .001) and diabetes (HR, 1.61; 95% CI, 1.36-1.92; P < .001) who were taking cilostazol. Conclusions: In patients undergoing LER, cilostazol use was associated with improved 1-year freedom from amputation. Patients with renal failure and diabetes also demonstrated a significant benefit from taking cilostazol. Further studies are needed to evaluate the benefits of cilostazol after LER. (J Vasc Surg 2015;-:1-5.)
Peripheral arterial disease (PAD) is a relatively common disease affecting the lives of millions of Americans, particularly men and women aged >40 years.1,2 Among patients with symptoms of claudication, the amputation rate is w1% to 3% in 5 years; however, overall mortality in this cohort of patients approaches 40% at 5 years.1 Cilostazol, an oral phosphodiesterase-3 inhibitor, is frequently used to treat patients with symptomatic claudication. Its effects are believed to be mediated by its vasodilatory properties as well as an inhibitory effect on platelet aggregation.3,4 In addition, newer studies suggest cilostazol may play a role in decreasing intimal hyperplasia after angioplasty and stenting in coronary vessels.5-7 From the Division of Vascular Surgery, Department of Surgerya and Department of Family and Community Medicine,b University of Missouri School of Medicine, Columbia; and the Department of Surgery, Rutgers-Robert Wood Johnson Medical School, New Brunswick.c Author conflict of interest: none. Presented at the Plenary Session of the Thirty-eighth Annual Meeting of the Midwestern Vascular Surgical Society, Coralville, Iowa, September 4-6, 2014. Reprint requests: Todd R. Vogel, MD, MPH, Department of Surgery, Division of Vascular Surgery, University of Missouri Hospital & Clinics, One Hospital Dr, Columbia, MO 65212 (e-mail: vogeltr@health. missouri.edu). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214 Copyright Ó 2015 by the Society for Vascular Surgery. http://dx.doi.org/10.1016/j.jvs.2014.11.067
In patients with PAD undergoing a lower extremity revascularization (LER) procedure, the goal of therapy is to prevent limb loss. This analysis evaluated the association between cilostazol use in the Medicare population and outcomes after LER procedures, including endovascular and open procedures for LER. METHODS This study was approved by the Institutional Review Boards at the University of Missouri School of Medicine and the Rutgers-Robert Wood Johnson Medical School. Informed patient consent was not needed because the Medicare data were deidentified. Data source. Data for this analysis were captured from the following Centers for Medicare & Medicaid Services files for the years 2007 to 2008: Medicare Provider Analysis and Review (MedPAR), Carrier Claim File, Part D Drug Event (PDE), and the Beneficiary Summary File. MedPAR data contain information for Medicare hospitalized patients, such as sociodemographic characteristics, diagnoses, procedures provided during the hospitalization, hospital length of stay, various charges, and patient outcomes at discharge. The Carrier Claim file provides information about surgical procedures using the Current Procedural Terminology 4 (CPT-4) procedure codes, which are more specific and detailed than the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) procedure codes. The PDE File, using 1
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2 Neel et al
the National Drug Codes (NDC), provides data on prescription drugs dispensed to Medicare beneficiaries. The Beneficiary Summary File covers Medicare enrollment, including Part D. The unique personal identifier for each Medicare beneficiary is the same in the different files, allowing linkage between these files. Study population. The analysis included Medicare beneficiaries aged $65 years who were electively hospitalized with a diagnosis of atherosclerosis of LE arteries for LER in 2007 to 2008 and had Part D coverage. From the Beneficiary Summary File, we selected individuals with enrollment in Medicare Part D for the entire calendar year. Then, using the MedPAR data, we selected from this cohort those who were hospitalized with a diagnosis of intermittent claudication (ICD-9-CM diagnosis code 440.21), rest pain (440.22), ulceration (440.23), or gangrene (440.24). Finally, using the Carrier File, we included in the study cohort only those patients who underwent LER by endovascular procedure (CPT-4 codes 35470, 35473, and 35474) or open surgery (35556, 35583, 35656 [femoral-popliteal bypass]; 35566, 35585, 35666 [femoral-tibial bypass]). Cilostazol use was identified with the following NDC codes in the Part D Drug Event File: 00054002821, 00185012305, 00185012360, 00185022305, 00185022360, 16590028530, 16590028560, 16590028590, 54868541100, 54868541101, 59148000216, 59148000316, 60429076260, 60429076305, 60429076360, 63629464401, 63629464402, 63629511201, 63629511202, 63629511203, 63629511204, 64720015806, 64720015906, and 64720015950. LE amputations were recognized with the CPT-4 codes 27590, 27591, 27592, 27880, 27881, 27882, 28800, 28805, 28810, 28820, and 28825. ICD-9-CM diagnosis codes for secondary diagnoses were used to identify postoperative complications: 997.1, 410.00-410.02, 410.10-410.12, 410.20-410.22, 410.30-410.32, 410.40410.42, 410.50-410.52, 410.60-410.62, 410.70-410.72, 410.80-410.82, 410.90-410.92, and 427.5 for cardiac complications, including myocardial infarction; 997.3x, 480.x, 481, 482.0-482.2, 482.3x, 482.4x, 482.8x, 482.9, 483.x, 484.x, 485, 486, 507.0, 512.1, 518.4, 518.5, 518.81, and 518.82 for respiratory complications and pneumonia; 997.5, 584.x, and 593.81 for renal complications and acute renal failure; 996.62, 998.30-998.32, 998.5x., and 999.3x for surgical infection; 998.11 for hemorrhage and 998.12 for hematoma complicating LER. Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project comorbidity software measures were used to evaluate comorbidities in the study population (available at http://www.hcup-us.ahrq.gov/ toolssoftware/comorbidity/comorbidity.jsp#download). We included in the analysis the following comorbid conditions: congestive heart failure, chronic pulmonary disease, pulmonary circulation disease, hypertension, diabetes, renal failure, and obesity. Statistical analysis. All analysis were performed with SAS 9.3 software (SAS Institute Inc, Cary, NC). The Student t-test was used to evaluate differences between
continuous variables. Differences between categoric variables were analyzed by c2 Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. We also computed 30-day, 90-day, and 1-year crude amputation rates. To take into account potential confounders while comparing these rates between study groups, we used stepwise multivariable logistic regression analysis with adjustment for age, gender, race, severity of disease (claudication, rest pain, or ulceration/gangrene), comorbidities, type of procedure (endovascular or open surgery), and cilostazol use. The 1-year freedom from amputation was analyzed with Kaplan-Meier survival curves and Cox proportional hazards regression, with adjustment by the same covariates as in the logistic regression models. We selected 789 patients (3.4%) who received cilostazol only after the procedure and compared them with patients who received cilostazol before the procedure (including those who continued taking medication after procedure) and patients who did not take cilostazol. P # .05 was considered statistically significant. RESULTS A total of 22,954 patients were selected for analysis: 1999 were prescribed cilostazol preoperatively and 20,955 were not. Among patients who received cilostazol before LER, 44.3% continued to receive it after the procedure. This proportion was approximately the same in patients with claudication (44.7%), rest pain (46.7%), and ulceration/gangrene (42.9%). Table I reports the characteristics of both groups. Although we found statistically significant differences in the mean age of patients between the two groups, this difference was not clinically important. Gender distribution in both groups was similar. Compared with those not taking cilostazol, the proportion of African Americans in the cilostazol group was smaller, and the proportion of Hispanics was greater. Patients with cilostazol had greater rates of hypertension and chronic pulmonary disease, whereas their counterparts experienced more renal failure. Approximately one-third of patients without preoperative cilostazol experienced claudication, and more than half had ulceration or gangrene. Conversely, almost half of patients in the group taking cilostazol had claudication compared with one-third who experienced ulceration or gangrene. In both groups, endovascular repairs predominated over open surgery. Patients who received cilostazol before LER compared with those without cilostazol demonstrated lower crude amputation rates at 30 days (7.8% vs 13.4%), 90 days (10.7% vs 18.0%), and 1 year (14.8% vs 24.0%; P < .0001 for all) after both endovascular repairs (Fig 1, A) and open surgery (Fig 1, B). In multivariable logistic regression analysis, however, we found a significant association of preoperative cilostazol use on amputation rates at 1 year postprocedure. Patients without cilostazol were more likely to undergo amputation during the year after the index procedure than those with cilostazol (OR, 1.19; 95% CI, 1.02-1.37; P ¼ .02). Patients receiving cilostazol after the procedure had no significant difference
JOURNAL OF VASCULAR SURGERY Volume -, Number -
Neel et al 3
Table I. Characteristics of the study population Treatment
Characteristicsa Age, years Age groups, years 65-69 70-74 75-79 $80 Gender Male Female Race/ethnicity White African American Hispanic Other and unknown Comorbidities Hypertension Chronic pulmonary disease Pulmonary circulation disease Diabetes Renal failure Obesity Atherosclerosis severity Claudication Rest pain Ulceration/gangrene Procedure Endovascular Open surgery
Without cilostazol (n ¼ 20,955)
With cilostazol (n ¼ 1999)
P
76.0 6 7.8
75.5 6 7.1
.006
5437 4370 4117 7031
(26.0) (20.8) (19.6) (33.6)
505 450 457 587
(25.3) .51 (22.5) .08 (22.9) .0006 (29.3)
