Abstract
Background
Target lesion revascularization (TLR) with primary percutaneous transluminal angioplasty (PTA) versus cryoplasty (CRYO) in the treatment of de novo femoropopliteal disease has not been well defined in randomized trials.
Methods
In this prospective, 2-center randomized trial of PTA vs CRYO of femoropopliteal arteries, the primary endpoint of TLR was evaluated at 6 months. Secondary endpoints included the rate of bail out stenting because of suboptimal acute angiographic results (defined as a residual narrowing of ≥30% or type C or higher dissection) and target vessel revascularization (TVR). Major adverse events including death and amputations were recorded. A two sample t test was used to compare the two groups on the continuous variables. For categorical variables, cross tabular analysis was conducted with nonparametric tests (Chi Square and Fisher’s Exact) used to test for significant differences.
Results
A total of 40 patients were included in the study. Of these 20 patients (24 vessels) were included in the PTA arm and 20 patients (26 vessels) in the CRYO arm. CRYO was performed at a predefined automated pressure of 8 atm. PTA was performed at a mean pressure of 9.57±1.34 atm ( P =.001 compared to CRYO). TLR (10.5% vs. 15%, P =NS) and TVR (10% vs 25%, P =NS) were statistically similar between the PTA arm compared to the CRYO arm respectively. Bail out stenting was performed in 10/24 (41.7%) of vessels in the PTA arm and 10/26 (38.5%) of patients in the CRYO arm ( P =NS).
Conclusion
In this pilot randomized study of de novo femoropopliteal lesions, CRYO and PTA had the same TLR and TVR at 6 months in treating femoropopliteal de novo lesions. Also, bail out stenting was statistically similar between the 2 groups. Larger studies are needed to confirm these results.
1
Purpose
Despite numerous advances in the percutaneous treatment of femoropopliteal vessels, restenosis and TLR rates at 1 year continue to be significant ranging from 15% to 50%. Cryoplasty (CRYO) with the PolarCath (Boston Scientific, Natick, Mass) uses nitrous oxide to cool the angioplasty balloon to −10 °C on contact with the lesion, an ideal temperature at which apoptosis of cells occurs. CRYO has been reported to have a high rate of acute success in both femoropopliteal and infrapopliteal lesions . Furthermore, CRYO was reported to have a clinical primary patency rate of 79% to 82% at 9 months and an overall need for bailout stenting ranging from 2.7% to 33% .
It remains unclear, however, whether CRYO has any advantage over PTA in reducing smooth muscle cell proliferation and restenosis in de novo lesions. Spiliopoulos et al. showed that CRYO in femoropopliteal percutaneous interventions showed no advantage over PTA for the endpoints of bailout stenting or need for repeat target vessel revascularization. In their study approximately 40% of their patients were treated for in-stent restenosis. Also, Jahnke at al. reported that CRYO had a statistically non-significant trend toward better patency rate at 9 months (79.3% vs 66.7%, P =.14) but no difference in bail out stenting compared to PTA (30% vs 39%, P =.34).
This study was conducted to compare the two approaches of CRYO versus primary angioplasty (PTA) in patients with de novo femoropopliteal lesions on TLR, improvement in ankle brachial index (ABI) and patients’ symptoms at 6 months follow-up.
2
Materials and methods
This is a 2-center, randomized trial in treating femoropopliteal de novo lesions using CRYO versus PTA. Patients were included if they had de novo lesions, were >18 years of age and referred for claudication (Rutherford Becker I–III) or critical limb ischemia (Rutherford Becker IV–V). They were excluded if they had one or more of the following: 1. heavily calcified vessels (as subjectively determined by the operator), 2. total occlusions longer than 10 cm, any lesion less than 3 cm, or non femoropopliteal lesions, 3. inability to take aspirin or adenosine diphosphate receptor antagonists, 4. bleeding disorder or platelet count less than 100,000 per µl, 5. creatinine over 3.5 mg/dl, 6. unwilling to give consent or return for future follow up visits, 7. decompensated congestive heart failure or acute coronary syndrome, and 8. staged vascular procedure during the same hospital stay or one week after the index procedure. The study was approved by the Institutional Board of each institution where the study was conducted. Informed consent was obtained on all patients.
The primary endpoint of the trial was TLR at 6 months. Secondary endpoints included:
- 1.
The rate of bail out stenting because of suboptimal acute angiographic results defined as a residual stenosis of ≥30% or the presence of type C–F dissection. Dissections were classified according to the National Heart, Lung, and Blood Institute classification for coronary artery dissections .
- 2.
Final acute angiographic results in each arm at the end of the procedure
- 3.
Target vessel revascularization (TVR) at 6 months
- 4.
Major adverse events including major amputation, death, distal embolization, vascular complications (arteriovenous fistula, pseudoaneurysm, or perforation), major bleeding (loss of 3 units of packed red blood cells with a source of bleed, or intracranial bleed or retroperitoneal bleed), unplanned urgent revascularization of the treated vessel in the same hospital stay, stroke, and acute renal failure (an increase in creatinine clearance by 25% over preprocedure baseline)
- 5.
Change in the ankle brachial index at 6 month post procedure from baseline.
2.1
Procedural steps
Clopidogrel 600 mg and aspirin 324 mg were administered orally immediately prior to the procedure in patients not taking antiplatelet agents. Patients who were already receiving clopidogrel and aspirin continued to take 75 mg oral clopidogrel and 324 mg oral aspirin daily. Patients with an elevated creatinine of ≥1.5 mg/dl were hydrated with 100 ml/h of 0.9% NaCl in the morning of the procedure for 2 to 5 h, and given 1 gm of acetylcysteine at least 1 h preprocedure. Iopamidol (Bracco Diagnostics Inc, Princeton, NJ) or ioversol (Mallinckrodt Inc, Hazelwood, MO) was utilized as contrast agent. Intravenous bivalirudin, 0.75-mg/kg bolus plus 1.75 mg/kg/h for the duration of procedure , was the exclusive anticoagulant administered during the procedure.
All femoropopliteal de novo lesions in the same patient that met the angiographic inclusion criteria were subjected to the same treatment arm. TransAtlantic Inter-Society Consensus I (TASC-I) D lesions were not included in this study. Randomization was performed after the peripheral angiogram was done and the lesions met the inclusion criteria. Femoropopliteal lesions more than 50% were included in the study. Lesion severity was qualitatively determined by the operator. Each femoropopliteal artery was divided into 4 segments: common femoral, superficial femoral, popliteal and profunda femoris. The use of embolic filters was not mandated in this protocol.
The CRYO device consisted of the PolarCath (Boston Scientific, Natick, Mass) that uses nitrous oxide to cool the angioplasty balloon to −10 °C on contact with the lesion. Lesions were treated at the automated pressure of 8 atm for 60 s . Two inflations were typically used to treat each lesion.
For patients enrolled in the PTA arm alone the balloon was used as a primary modality on all lesions. Procedural success was defined as residual stenosis of <30% with no dissection of type C–F. Balloon inflation pressure was initially started at 8 atm but increased to obtain a full waist on the balloon as per operator discretion.
Procedural failure was defined as a residual lesion stenosis of ≥30% and/or a type C–F dissection using PTA alone or CRYO. Bail out stenting was performed in patients with procedural failure using the nitinol self-expanding LIFESTENT (Bard Peripheral Vascular Inc, Tempe, AZ) and Protégé stents (ev3, Plymouth, MN). Stents were sized at 1–2 mm above the estimated vessel diameter. Stents were not permitted for procedural success. At the end of the procedure, closure devices were used at the discretion of the operator.
Patients were followed in the office at 1 month and 6 months post procedure. Rutherford Becker class and ankle brachial index were performed during these visits.
2.2
Statistical assumptions and analysis
Simple randomization was performed on a 1:1 basis using sealed envelopes. Clinical, demographics, and detailed angiographic variables were documented on electronic case report forms. Case report forms and events were monitored by an independent monitor. Chi-square and t test were used to compare dichotomous and continuous variables respectively. SPSS (IBM, Chicago, IL) statistical software was used. In this small pilot study no statistical assumptions are made.
2
Materials and methods
This is a 2-center, randomized trial in treating femoropopliteal de novo lesions using CRYO versus PTA. Patients were included if they had de novo lesions, were >18 years of age and referred for claudication (Rutherford Becker I–III) or critical limb ischemia (Rutherford Becker IV–V). They were excluded if they had one or more of the following: 1. heavily calcified vessels (as subjectively determined by the operator), 2. total occlusions longer than 10 cm, any lesion less than 3 cm, or non femoropopliteal lesions, 3. inability to take aspirin or adenosine diphosphate receptor antagonists, 4. bleeding disorder or platelet count less than 100,000 per µl, 5. creatinine over 3.5 mg/dl, 6. unwilling to give consent or return for future follow up visits, 7. decompensated congestive heart failure or acute coronary syndrome, and 8. staged vascular procedure during the same hospital stay or one week after the index procedure. The study was approved by the Institutional Board of each institution where the study was conducted. Informed consent was obtained on all patients.
The primary endpoint of the trial was TLR at 6 months. Secondary endpoints included:
- 1.
The rate of bail out stenting because of suboptimal acute angiographic results defined as a residual stenosis of ≥30% or the presence of type C–F dissection. Dissections were classified according to the National Heart, Lung, and Blood Institute classification for coronary artery dissections .
- 2.
Final acute angiographic results in each arm at the end of the procedure
- 3.
Target vessel revascularization (TVR) at 6 months
- 4.
Major adverse events including major amputation, death, distal embolization, vascular complications (arteriovenous fistula, pseudoaneurysm, or perforation), major bleeding (loss of 3 units of packed red blood cells with a source of bleed, or intracranial bleed or retroperitoneal bleed), unplanned urgent revascularization of the treated vessel in the same hospital stay, stroke, and acute renal failure (an increase in creatinine clearance by 25% over preprocedure baseline)
- 5.
Change in the ankle brachial index at 6 month post procedure from baseline.
2.1
Procedural steps
Clopidogrel 600 mg and aspirin 324 mg were administered orally immediately prior to the procedure in patients not taking antiplatelet agents. Patients who were already receiving clopidogrel and aspirin continued to take 75 mg oral clopidogrel and 324 mg oral aspirin daily. Patients with an elevated creatinine of ≥1.5 mg/dl were hydrated with 100 ml/h of 0.9% NaCl in the morning of the procedure for 2 to 5 h, and given 1 gm of acetylcysteine at least 1 h preprocedure. Iopamidol (Bracco Diagnostics Inc, Princeton, NJ) or ioversol (Mallinckrodt Inc, Hazelwood, MO) was utilized as contrast agent. Intravenous bivalirudin, 0.75-mg/kg bolus plus 1.75 mg/kg/h for the duration of procedure , was the exclusive anticoagulant administered during the procedure.
All femoropopliteal de novo lesions in the same patient that met the angiographic inclusion criteria were subjected to the same treatment arm. TransAtlantic Inter-Society Consensus I (TASC-I) D lesions were not included in this study. Randomization was performed after the peripheral angiogram was done and the lesions met the inclusion criteria. Femoropopliteal lesions more than 50% were included in the study. Lesion severity was qualitatively determined by the operator. Each femoropopliteal artery was divided into 4 segments: common femoral, superficial femoral, popliteal and profunda femoris. The use of embolic filters was not mandated in this protocol.
The CRYO device consisted of the PolarCath (Boston Scientific, Natick, Mass) that uses nitrous oxide to cool the angioplasty balloon to −10 °C on contact with the lesion. Lesions were treated at the automated pressure of 8 atm for 60 s . Two inflations were typically used to treat each lesion.
For patients enrolled in the PTA arm alone the balloon was used as a primary modality on all lesions. Procedural success was defined as residual stenosis of <30% with no dissection of type C–F. Balloon inflation pressure was initially started at 8 atm but increased to obtain a full waist on the balloon as per operator discretion.
Procedural failure was defined as a residual lesion stenosis of ≥30% and/or a type C–F dissection using PTA alone or CRYO. Bail out stenting was performed in patients with procedural failure using the nitinol self-expanding LIFESTENT (Bard Peripheral Vascular Inc, Tempe, AZ) and Protégé stents (ev3, Plymouth, MN). Stents were sized at 1–2 mm above the estimated vessel diameter. Stents were not permitted for procedural success. At the end of the procedure, closure devices were used at the discretion of the operator.
Patients were followed in the office at 1 month and 6 months post procedure. Rutherford Becker class and ankle brachial index were performed during these visits.
2.2
Statistical assumptions and analysis
Simple randomization was performed on a 1:1 basis using sealed envelopes. Clinical, demographics, and detailed angiographic variables were documented on electronic case report forms. Case report forms and events were monitored by an independent monitor. Chi-square and t test were used to compare dichotomous and continuous variables respectively. SPSS (IBM, Chicago, IL) statistical software was used. In this small pilot study no statistical assumptions are made.
3
Results
Forty patients were included in the study. Of these, 20 patients (26 vessels) were randomized to the cryoplasty arm and 20 patients (24 vessels) to the PTA arm. Baseline clinical and demographic variables were all similar between the 2 groups with the exception of body mass index that was higher in the CRYO group and cerebrovascular disease that was more prevalent in the angioplasty group ( Table 1 ). There was a high incidence of diabetes and hypertension and a modestly high baseline hs-CRP in the entire cohort. Approximately 15% of patients had critical limb ischemia and 80% were claudicants. All procedures were performed on an elective basis. Baseline procedural variables were also well matched between the 2 groups. Lesion length, pre-stenosis severity, TASC A-C lesions (using TASC I classification), and number of tibial runoffs were all similar between the 2 groups. There was a higher, statistically non significant, prevalence of moderately calcified vessels in the CRYO group ( Table 2 ).
| n | Balloon mean/% | n | Cryoplasty mean/% | P | |
|---|---|---|---|---|---|
| Age (years) | 20 | 69.8±9.8 | 20 | 64.4±11 | NS |
| BMI | 20 | 27.3±5.6 | 20 | 31.5±6.8 | .039 |
| Hs-CRP (mg/l) | 18 | 3.9±5.3 | 18 | 3.4±2.5 | NS |
| ABI of treated leg at rest | 17 | 0.79±0.16 | 18 | 0.77±0.19 | NS |
| ABI of treated leg with exercise | 13 | 0.46±0.14 | 15 | 0.44±0.17 | NS |
| Run off of treated leg | 20 | 1.9±1.0 | 20 | 2.2±0.8 | NS |
| Males (%) | 11/20 | 55 | 8/20 | 40 | NS |
| Tobacco | 20 | NS | |||
| Never (%) | 1/20 | 5 | 3/20 | 15 | |
| Past (%) | 11/20 | 55 | 3/20 | 15 | |
| Current (%) | 8/20 | 40 | 14/20 | 70 | |
| Bypass surgery | 2/20 | 10 | 1/20 | 5 | NS |
| Carotid endarterectomy | 1/20 | 5 | 1/20 | 5 | NS |
| Coronary artery disease | 11/20 | 55 | 10/20 | 50 | NS |
| Congestive heart failure | NS | ||||
| A | 15/20 | 75 | 15/20 | 75 | |
| B | 1/20 | 5 | 1/20 | 5 | |
| C | 4/20 | 20 | 4/20 | 20 | |
| Renal insufficiency | 5/20 | 25 | 4/20 | 20 | NS |
| Chronic lung disease | 2/20 | 10 | 0/20 | 0 | NS |
| Peripheral vascular disease | 17/20 | 85 | 15/20 | 75 | NS |
| Abdominal aortic aneurysm | 2/20 | 10 | 0/20 | 0 | NS |
| Cerebrovascular disease | 5/20 | 25 | 0/20 | 0 | .047 |
| Hypertension | 15/20 | 75 | 17/20 | 85 | NS |
| Hypercholesterolemia | 18/20 | 90 | 17/20 | 85 | NS |
| Diabetes | 8/20 | 40 | 10/20 | 50 | NS |
| Rutherford class | NS | ||||
| 2/3 | 17/20 | 85 | 17/20 | 85 | |
| 4/5 | 3/20 | 15 | 3/20 | 15 | |
| Aspirin | 19/19 | 100 | 20/20 | 100 | NS |
| Plavix/Ticlid | 20/20 | 100 | 20/20 | 100 | NS |
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