Long-Term Evaluation of Indobufen in Peripheral Vascular Disease
G.
Belcaro, M.D. , F.I.C.A.* and P. De
Simone, M.D.**
CHIETI and MILAN, ITALY
Abstract Indobufen—an inhibitor of platelets aggregation—has been used in 306 patients with intermittent claudication due to peripheral vascular disease. Patients were treated and followed up for one year. One patient of every 3 treated with indobufen was treated with ASA, and a control group of patients receiving no treatment was also followed up. The authors studied by means of a treadmill exercise test the pain-free walking distance (PFWD), the global walking distance (GWD), and the recovery time after exercise. The treatment period was completed by 290 patients: 204 claudicants, 51 claudicants with diabetes, and 35 with a short PFWD and GWD (>150 m). Indobufen was more effective than ASA in improving the PFWD and GWD in all groups. There were also fewer side effects with indobufen, and cardiac morbidity and mortality was also reduced. In conclusion indobufen showed its activity and safety in chronic treatment of patients with peripheral disease, and we suggest that it may be used for long periods without side effects.
Introduction with peripheral vascular disease (intermittent claudication and rest pain) there is a high level of cardiovascular risk, not only for periperal disease but also for cardiac and cerebrovascular events. In
patients
These
patients are usually chronically treated with antiplatelet agents. There are special requirements for effective antiplatelet treatment or prophylaxis. Because it is chronic and may last for the rest of the life of the patients, it must be inexpensive and simple and must have a low incidence of side effects. It must also significantly reduce cardiovascular morbidity and mortality. Cumulative evaluation of many clinical studies on antiplatelet agents showed that they produce a significant reduction in vascular mortality, an
I
particularly of nonfatal myocardial infarction and nonfatal stroke.’ From the *Laboratorio di Microcircolazione Cardiovascular Institute Universita’ Abruzzese G.D’ Annunzio, Chieti; and **Farmitalia-C. Erba, Milan, Italy
8
9
Antiplatelet Treatment with Indobufen Indobufen is an inhibitor of platelets aggregation that acts on cyclooxigenase to block the conversion of arachidonic acid to cyclic endoperoxides, these being the unstable precursors of tromboxane A2 and prostaglandins.2-4 Indobufen has been widely used in the last ten years as an antiplatelet agent in patients with vascular disease. It is chronically used for indications such as ischemic cardiac disease, cerebral and peripheral vascular disease, diabetic microangiopathy and venous and other vascular problems. In two previous reviews we presented data concerning short-term (four weeks) efficacy and safety of indobufen in 435 vascular patients, and its long-term efficacy and safety were evaluated in a subsequent study of 6 1428 vascular patients monitored for about six years.6 The aim of this study was the evaluation of long-term efficacy and tolerability in patients with peripheral vascular disease monitored for one year. We also evaluated the efficacy of indobufen in comparison with acetylsalycilic acid (ASA). Patients and Methods
patients with periperal vascular signs and symptoms but no other clinical evidence of cardiac or peripheral vascular disease. After giving informed consent to the study, patients were divided We selected
into three groups: group
I-patients receiving indobufen (one tablet, 200 mg, bid)
group 2-patients receiving ASA (soluble tablet, 0.5 g, group 3--controls
bid)
(no pharmacologic treatment).
The control group was made up of patients who were unable to follow any kind of treatment (either because they refused it or because they had important gastrointestinal symptoms).
One
patient of every 3 treated with indobufen was given treatment with ASA. Smokers (76% of patients) had quit smoking at least three weeks before entering the study: patients were asked to walk at least two periods of thirty minutes per day. They were also asked to avoid any other drug and follow a diet normal for calories and fat content. Criteria, of exclusion were poorly controlled diabetes, age less than forty or more than eighty years, hypertension requiring, drug treatment, tumors, reduced left ventricular output, coagulation disorders and other serious diseases, and diffuse vascular disease. Patients were followed up in our, cardiovascular laboratory with noninvasive tests: duplex scanning (simultaneous B-mode ultrasound plus Doppler) and angiodynography (color duplex scanning), blood tests to evaluate lipids, liver and renal functions, and ECG. Blood pressure (ankle/foot and upper limbs) was also monitored. These tests were repeated twice a year. Patients were studied with an exercise (treadmill) test using two standard procedures: Treadmill Test 1: This test was made to evaluate the pain-free walking distance (PFWD) and the total walking distance (TWD). function
was
operated at 4 km/hour with 10% inclination while, cardiac continued until pain in the lower extremity muscles stopped the
The treadmill
monitored. The test
was
was
patient. Treadmill Test 2: The patient was asked to walk five minutes at 4 km/hr (
fall in pressure at the end of the exercise to reach the preexercise ankle pressure.
10% slope). The subsequent was recorded with the recovery time (RT~the time necessary
10
According to their clinical characteristics we divided patients into claudicants, diabetic claudicants, and patients with short distance claudication. Patients within these groups, were homogeneously distributed and when first studied had a comparable clinical picture, distribution, and localization of lesions (observed by duplex scanning and/or angiodynography). None of these patients underwent angiography for we consider it only in patients who are definitely going to be treated surgically. The statistical evaluation was made using the Mann-Whitney U-test and the ANOVA test. Results Of a total of 306
patients included in the study 290 completed the one-year treatment period. Fifteen had a cardiac problem and had to be treated with other drugs. For this reason they were patients (5.2%) excluded. One patient (0.33%) died of acute myocardial infarction. The three groups of patients were not
Table I. in 204 Claudication Patients Treated with Indobufen (Group of Intermittent Tr~~!g/~. Control GroM/) 2), o~J (3) ~/f/! with A~o (Group 2), (G/Y)M/? and
G.
Belcaro, M.D. , F.I.C.A.* and P. De
Simone, M.D.**
CHIETI and MILAN, ITALY
Abstract Indobufen—an inhibitor of platelets aggregation—has been used in 306 patients with intermittent claudication due to peripheral vascular disease. Patients were treated and followed up for one year. One patient of every 3 treated with indobufen was treated with ASA, and a control group of patients receiving no treatment was also followed up. The authors studied by means of a treadmill exercise test the pain-free walking distance (PFWD), the global walking distance (GWD), and the recovery time after exercise. The treatment period was completed by 290 patients: 204 claudicants, 51 claudicants with diabetes, and 35 with a short PFWD and GWD (>150 m). Indobufen was more effective than ASA in improving the PFWD and GWD in all groups. There were also fewer side effects with indobufen, and cardiac morbidity and mortality was also reduced. In conclusion indobufen showed its activity and safety in chronic treatment of patients with peripheral disease, and we suggest that it may be used for long periods without side effects.
Introduction with peripheral vascular disease (intermittent claudication and rest pain) there is a high level of cardiovascular risk, not only for periperal disease but also for cardiac and cerebrovascular events. In
patients
These
patients are usually chronically treated with antiplatelet agents. There are special requirements for effective antiplatelet treatment or prophylaxis. Because it is chronic and may last for the rest of the life of the patients, it must be inexpensive and simple and must have a low incidence of side effects. It must also significantly reduce cardiovascular morbidity and mortality. Cumulative evaluation of many clinical studies on antiplatelet agents showed that they produce a significant reduction in vascular mortality, an
I
particularly of nonfatal myocardial infarction and nonfatal stroke.’ From the *Laboratorio di Microcircolazione Cardiovascular Institute Universita’ Abruzzese G.D’ Annunzio, Chieti; and **Farmitalia-C. Erba, Milan, Italy
8
9
Antiplatelet Treatment with Indobufen Indobufen is an inhibitor of platelets aggregation that acts on cyclooxigenase to block the conversion of arachidonic acid to cyclic endoperoxides, these being the unstable precursors of tromboxane A2 and prostaglandins.2-4 Indobufen has been widely used in the last ten years as an antiplatelet agent in patients with vascular disease. It is chronically used for indications such as ischemic cardiac disease, cerebral and peripheral vascular disease, diabetic microangiopathy and venous and other vascular problems. In two previous reviews we presented data concerning short-term (four weeks) efficacy and safety of indobufen in 435 vascular patients, and its long-term efficacy and safety were evaluated in a subsequent study of 6 1428 vascular patients monitored for about six years.6 The aim of this study was the evaluation of long-term efficacy and tolerability in patients with peripheral vascular disease monitored for one year. We also evaluated the efficacy of indobufen in comparison with acetylsalycilic acid (ASA). Patients and Methods
patients with periperal vascular signs and symptoms but no other clinical evidence of cardiac or peripheral vascular disease. After giving informed consent to the study, patients were divided We selected
into three groups: group
I-patients receiving indobufen (one tablet, 200 mg, bid)
group 2-patients receiving ASA (soluble tablet, 0.5 g, group 3--controls
bid)
(no pharmacologic treatment).
The control group was made up of patients who were unable to follow any kind of treatment (either because they refused it or because they had important gastrointestinal symptoms).
One
patient of every 3 treated with indobufen was given treatment with ASA. Smokers (76% of patients) had quit smoking at least three weeks before entering the study: patients were asked to walk at least two periods of thirty minutes per day. They were also asked to avoid any other drug and follow a diet normal for calories and fat content. Criteria, of exclusion were poorly controlled diabetes, age less than forty or more than eighty years, hypertension requiring, drug treatment, tumors, reduced left ventricular output, coagulation disorders and other serious diseases, and diffuse vascular disease. Patients were followed up in our, cardiovascular laboratory with noninvasive tests: duplex scanning (simultaneous B-mode ultrasound plus Doppler) and angiodynography (color duplex scanning), blood tests to evaluate lipids, liver and renal functions, and ECG. Blood pressure (ankle/foot and upper limbs) was also monitored. These tests were repeated twice a year. Patients were studied with an exercise (treadmill) test using two standard procedures: Treadmill Test 1: This test was made to evaluate the pain-free walking distance (PFWD) and the total walking distance (TWD). function
was
operated at 4 km/hour with 10% inclination while, cardiac continued until pain in the lower extremity muscles stopped the
The treadmill
monitored. The test
was
was
patient. Treadmill Test 2: The patient was asked to walk five minutes at 4 km/hr (
fall in pressure at the end of the exercise to reach the preexercise ankle pressure.
10% slope). The subsequent was recorded with the recovery time (RT~the time necessary
10
According to their clinical characteristics we divided patients into claudicants, diabetic claudicants, and patients with short distance claudication. Patients within these groups, were homogeneously distributed and when first studied had a comparable clinical picture, distribution, and localization of lesions (observed by duplex scanning and/or angiodynography). None of these patients underwent angiography for we consider it only in patients who are definitely going to be treated surgically. The statistical evaluation was made using the Mann-Whitney U-test and the ANOVA test. Results Of a total of 306
patients included in the study 290 completed the one-year treatment period. Fifteen had a cardiac problem and had to be treated with other drugs. For this reason they were patients (5.2%) excluded. One patient (0.33%) died of acute myocardial infarction. The three groups of patients were not
Table I. in 204 Claudication Patients Treated with Indobufen (Group of Intermittent Tr~~!g/~. Control GroM/) 2), o~J (3) ~/f/! with A~o (Group 2), (G/Y)M/? and
