Peripheral artery disease (PAD) is a progressive disease with significant morbidity and mortality, which affects 4% to 12% of people aged 55 to 70 years and 20% of people are over 70 years old. And every year it causes 500,000 hospitalizations and 100,000 angiograms in the USA. On the one hand, PAD is a manifestation of atherosclerosis in the peripheral artery. In the peripheral arteries, a thrombus superimposed on atherosclerosis leads to the formation of PAD which may result in intermittent claudication (a kind of leg pain when walking and can be relieved by rest), ischemic necrosis, and, potentially, loss of the limb. On the other hand, peripheral arterial disease is a marker for systemic atherosclerosis. The risk of acute myocardial infarction (AMI) is increased by 20%-60% in PAD patients, and their risk of coronary death increases 2-6 fold. The annual overall major vascular event rate (acute myocardial infarction, ischemic stroke and vascular death) is 5%-7% in PAD patients.
The mainstay of treatment for patients with PAD is cardiovascular risk factor modification. The treatment consists of smoking cessation, prescribed exercise, antiplatelet treatment, lipid-lowering therapy and control of blood pressure and diabetes. But some patients may not be able to comply with prescribed exercise due to associated comorbidity or social reasons. Thus, compliance with best medical treatment is poor. Meanwhile, as angioplasty or surgery are only used in severe, disabling or progressive intermittent claudication, those patients with milder symptoms may benefit from adjunctive therapy such as medical therapy.
Many drugs such as anti-hyperlipidemia drugs, carnitine and anti-platelet drugs are commonly used in the treatment of PAD. The use of anti-platelet drugs is not only beneficial to the treatment of peripheral vascular diseases, but also can reduce the risk of cardiovascular events. Currently, pentoxifylline and cilostazol are the only drugs approved by the FDA to treat peripheral artery disease.
Case Study
Arterial fibrillation (AF) remains the most frequently encountered arrhythmia in clinical practice and is a major cause of morbidity and mortality in PAD patients. On the other hand, Cilostazol can not only be used to increase walking distance from patients with intermittent claudication and lower the incidence of cardiac death and major cardiac events in PAD patients, but also be effective in the treatment of arrhythmias by affecting the heart automaticity. Prolonged total atrial conduction time (TACT) may be indicative of the electro-anatomical substrate for AF as it is associated with underlying CV disease and age. Accordingly, we aim to determine the effect of cilostazol treatment on TACT in PAD patients.
Patient enrollment is a key challenge to most clinical trials. First of all, the definition of PAD is critical, and the patient recruitment criteria changes accordingly. In this study, PAD was defined as follows: (i) typical or atypical symptoms in the lower leg or foot during exercise with an ankle brachial index (ABI) <0.9; (ii) patients with an ABI of 0.9-1.3, a post-exercise ABI <0.9. In addition, patients with the following symptoms were excluded: with a history of myocardial infarction (MI), unstable angina or coronary revascularization, heart failure with a left ventricular ejection fraction (LVEF) <50%, a history of stroke, chronic kidney failure (estimated glomerular filtration rate <30mL•min•1.73 m), a history of MI or coronary revascularization, coronary artery stenosis >40%, permanent or paroxysmal AF, bundle branch block or any other conduction defect on echocardiography (ECG), pacemaker implantation, thyroid disease, chronic obstructive pulmonary disease or valvular disorder, chronic alcoholism.
Another challenge is statistical analysis. We used SPSS v.11.5.0 for Windows (SPSS, Inc., Chicago, IL) for statistical analyses. Data are presented as mean ± SD. The Kolmogorov-Smirnov test was used to assess the normality of data distribution. Comparisons between baseline and post treatment were performed using the paired samples t-test. The correlation between the percentage of change in the TACT and the echocardiographic E/A ratio was examined using Spearman’s test. The level of statistical significance was set at p<0.05.
Using this definition and statistical strategy, we recruited appropriate patients and analyzed results from a trial of the effect of Cilostazol treatment on TACT in PAD patients.
Design:
A multicenter, randomized, placebo-controlled, double-blind and parallel group trial, including complete eligibility criteria, data collection schedule and detailed statistical analysis.
Participants:
There are 30 patients who are diagnosed with PAD. All recruited patients all had performance as follows:
- Patients perform typical or atypical symptoms in the lower leg or foot during exercise with an ankle brachial index (ABI) <0.9.
- Patients are with an ABI of 0.9-1.3, a post-exercise ABI <0.9.
- They don’t exhibit any electrolyte abnormality that can affect TACT and critical limb ischemia.
Length of Enrollment Period:
16 months.
Interventions:
We offered supervised exercise and smoking cessation to all patients, and they also started high blood pressure, diabetes and dyslipidemia management. None of the patients received any anti-arrhythmic drugs in addition to current medications. Thirty patients with peripheral artery disease were treated with cilostazol (200 mg/day) for 6 months. The baseline echocardiographic total atrial conduction time parameter was compared with the 6-month follow-up. And at baseline and the 6-month follow-up, all the patients underwent ECG and 2-dimensional transthoracic ECG with TDI.
Results:
Post cilostazol treatment, the mean HR increased significantly (65.7 ± 9.1 bpm vs. 74.3 ± 10.4 bpm, p<0.005). There was no significant change in systolic or diastolic blood pressure post treatment (systolic: 124.9 ± 10.3 mmHg vs. 127.0 ± 11.1 mmHg, p=0.118; diastolic: 81.1 ± 6.5 mmHg vs. 81.9 ± 7.3 mmHg, p=0.217). LVEF, LV enddiastolic (LVED) diameter, LV end-systolic (LVES) diameter and LA diameter did not differ after 6 months of treatment, as compared to baseline. E and A velocities did not change significantly, but the E/A ratio increased significantly after 6 months of cilostazol treatment (0.66 ± 0.15 vs. 0.73 ± 0.21, p<0.021). There were no significant changes in interventricular septal thickness, posteriorwall thickness or deceleration time of the E-wave after 6 months of treatment. The TACT duration was decreased to all patients after therapy compared to basal levels (121.8 ± 19.3 ms vs. 109.1 ± 15.9 ms, p0.001). When we corrected for HR by dividing E/A ratio and TACT by the square root of the R-R interval, a significant statistical difference was observed (Table 1). The percentage of change in TACT duration was strongly correlated with the percentage of change in the E/A ratio (r = ‒0.48, P<0.003) (Figure 3).
Figure 3. Correlation of TACT percentage change to E/A percentage change
Table 1. Echocardiographic and hemodynamic data before and after oral administration of cilostazol.
Data are shown as a number (%) or mean ± S.D. HR: heart rate; BP: blood pressure; LAD: left atrial dimension; IVST: interventricular septal thickness; PWT: posterior wall thickness; LVEDd: left ventricular end-diastolic diameter; LVESd: left ventricular end-systolic diameter; LVEF: left ventricular ejection fraction; E velocity: peak early mitral flow velocities; A velocity: peak late mitral flow velocities; E/A: the ratio of mitral E and A; DT: deceleration time of the E-wave; TAC: total atrial conduction time.
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References:
1. Alizade, E., et al. (2013) ‘Cilostazol decreases total atrial conduction time in patients with peripheral artery disease’, Journal of the American College of Cardiology, 62(18), C138-C138.
2. Bedenis, R., Stewart, M., Cleanthis, M., Robless, P., Mikhailidis, D. P., Stansby, G. (2014) ‘Cilostazol for intermittent claudication’, The Cochrane Library. John Wiley & Sons, Ltd.
3. Salhiyyah, K., Palfreyman, S. S., Booth, A., Michaels, J. A., Senanayake, E. (2005) ‘Pentoxifylline for intermittent claudication’, The Cochrane Library. John Wiley & Sons, Ltd.