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Therapeutic Apheresis and Dialysis 2014; 18(1):1–8 doi: 10.1111/1744-9987.12051 © 2013 The Authors Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis
Randomized Pilot Trial Between Prostaglandin I2 Analog and Anti-Platelet Drugs on Peripheral Arterial Disease in Hemodialysis Patients Takayasu Ohtake,1 Motoyoshi Sato,2 Ryoichi Nakazawa,3 Morihiro Kondoh,4 Takehiko Miyaji,5 Hidekazu Moriya,6 Sumi Hidaka,1 and Shuzo Kobayashi1 1
Department of Nephrology, Immunology, and Vascular Medicine, Shonan Kamakura General Hospital, Kamakura, 2Department of Kidney and Dialysis, Social Insurance Chukyo Hospital, Nagoya, 3Department of Nephrology, Mito Central Hospital, Mito, 4Department of Nephrology, Rakuwakai Otowa Memorial Hospital, Kyoto, 5Miyaji Hospital, Shizuoka, 6Department of Internal Medicine, Shonan Atsugi Hospital, Atsugi, Japan
Abstract: The effect of the prostaglandin I2 analog, beraprost sodium (BPS), on hemodialysis (HD) patients with peripheral arterial disease (PAD) has not been fully elucidated.The effect of BPS was compared to that of PAD drugs in HD patients with PAD in a multicenter randomized prospective interventional pilot study (J-PADD). Seventytwo PAD patients on HD were entered and randomly divided into two groups; that is, BPS group (Group A: n = 35) and PAD drug (cilostazol or sarpogrelate) group (Group B: n = 37). Primary endpoint was changes in skin perfusion pressure (SPP). Kidney Disease Quality of Life (KDQOL) score, cardiovascular events, PAD events, and adverse events were also evaluated. SPP increased significantly in both groups at 24 weeks from their basal levels.The absolute increase of SPP in Group A and Group B were
15.4 ⫾ 30.0 mm Hg (P < 0.0001) and 20.2 ⫾ 22.1 mm Hg (P = 0.025) (instep), and 13.8 ⫾ 19.3 mm Hg (P < 0.0001) and 9.2 ⫾ 16.3 mm Hg (P = 0.041) (sole), respectively. Changes of KDQOL score showed significantly better result in the role of physical score in Group A compared with Group B. Although heart rate was unchanged in Group A, 9.3/min increase was seen in Group B patients who received cilostazol. There was no intergroup difference in cardiovascular events and/or PAD events between the two groups during the study period. This exploratory pilot study suggested BPS was as effective as anti-platelet drugs in improving microcirculation in HD patients. Key Words: Beraprost sodium, Hemodialysis, Kidney disease quality of life, Peripheral arterial disease, Skin perfusion pressure.
Peripheral arterial disease (PAD) is common (1,2), and has a significant impact on mortality in patients on HD (3). Once they undergo a major amputation of a lower limb due to PAD, the 1-year survival rate falls to almost 50% (4), and it is almost comparable to the 1-year survival rate after acute myocardial infarction (AMI) in HD patients (5). Therefore, it is very important to diagnose and treat PAD in HD patients with effective drugs before they develop symptoms of critical limb ischemia (CLI).
Inter-Society Consensus for the Management of PAD (Trans-Atlantic Inter-Society Consensus II: TASCII) recommends the PAD drug cilostazol and serotonin type 2 inhibitor naftidrofuryl because they have evidence-based clinical utility in claudication (6). Cilostazol may be recommended for the treatment of PAD in HD patients as well as in the general population. However, use of cilostazol is contraindicated for patients with congestive heart failure (CHF). HD patients face the potential risk of having CHF by ischemic heart disease, valvular disease, or volume overload. Therefore, great care must be exercised when cilostazol is selected for the treatment of PAD in HD patients. As for naftidrofuryl, it is not approved for use in Japan. Instead of naftidrofuryl, sarpogrelate is used as a PAD drug with similar
Received December 2012; revised January 2013. Address correspondence and reprint requests to Dr Takayasu Ohtake, Department of Nephrology, Immunology, and Vascular Medicine, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura 247-8533, Japan. Email: [email protected]
1
2
T Ohtake et al.
pharmaceutical action as naftidrofuryl, and sarpogrelate has been reported to have a beneficial effect for intermittent claudication (7). Beraprost sodium (BPS) is an oral active prostaglandin I2 analog with several beneficial actions including anti-platelet effects, vasodilation, inhibitory effect of vascular smooth muscle cell growth, and protective effect on vascular endothelial cells (8–10). However, BPS is not recommended in TASC II as a drug for PAD because it has not yet reached final consensus. While there was a negative trial in the USA (11), there was a positive trial in Europe (12). Large randomized interventional studies for the treatment of PAD have been accumulating in the general population. However, they are still lacking in a HD population. Therefore, our purpose in this study was to clarify the efficacy and safety of BPS in HD patients with PAD with a multicenter randomized prospective open-label interventional pilot study (Japanese Peripheral Arterial Disease study in patients with chronic hemoDialysis: J-PADD). PATIENTS AND METHODS Patients and study protocol This study was performed in accordance with the Declaration of Helsinki. Eligible patients were asked about symptoms of PAD including chillness, numbness, ischemic claudication, and resting pain. Previous histories of intervention (percutaneous peripheral intervention or bypass surgery) or amputation due to PAD were also registered. All patients then underwent physiological examination about skin color, warmth, pulse exam of femoral artery, popliteal artery, dorsal artery, posterior tibial artery, and skin lesions, including ulcers and gangrene. This symptomatic information, previous histories of intervention or amputation, and physiological examinations including ankle-brachial pressure index (ABI), toebrachial pressure index (TBI), and skin perfusion pressure (SPP) were basically used to assign a limb ischemia according to the PAD severity classification criteria set by Fontaine et al. (13) When patients fulfilled any ischemic symptoms with at least one abnormality among ABI < 0.9, TBI < 0.6, SPP < 50 mm Hg, or had apparent previous history of intervention or amputation of lower limbs, they were defined as having PAD. Eligible subjects must fulfill all three inclusion criteria for this study, that is, (i) HD patient with PAD (Fontaine classification I–IV) (13), (ii) levels of SPP of instep or sole
Therapeutic Apheresis and Dialysis 2014; 18(1):1–8 doi: 10.1111/1744-9987.12051 © 2013 The Authors Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis
Randomized Pilot Trial Between Prostaglandin I2 Analog and Anti-Platelet Drugs on Peripheral Arterial Disease in Hemodialysis Patients Takayasu Ohtake,1 Motoyoshi Sato,2 Ryoichi Nakazawa,3 Morihiro Kondoh,4 Takehiko Miyaji,5 Hidekazu Moriya,6 Sumi Hidaka,1 and Shuzo Kobayashi1 1
Department of Nephrology, Immunology, and Vascular Medicine, Shonan Kamakura General Hospital, Kamakura, 2Department of Kidney and Dialysis, Social Insurance Chukyo Hospital, Nagoya, 3Department of Nephrology, Mito Central Hospital, Mito, 4Department of Nephrology, Rakuwakai Otowa Memorial Hospital, Kyoto, 5Miyaji Hospital, Shizuoka, 6Department of Internal Medicine, Shonan Atsugi Hospital, Atsugi, Japan
Abstract: The effect of the prostaglandin I2 analog, beraprost sodium (BPS), on hemodialysis (HD) patients with peripheral arterial disease (PAD) has not been fully elucidated.The effect of BPS was compared to that of PAD drugs in HD patients with PAD in a multicenter randomized prospective interventional pilot study (J-PADD). Seventytwo PAD patients on HD were entered and randomly divided into two groups; that is, BPS group (Group A: n = 35) and PAD drug (cilostazol or sarpogrelate) group (Group B: n = 37). Primary endpoint was changes in skin perfusion pressure (SPP). Kidney Disease Quality of Life (KDQOL) score, cardiovascular events, PAD events, and adverse events were also evaluated. SPP increased significantly in both groups at 24 weeks from their basal levels.The absolute increase of SPP in Group A and Group B were
15.4 ⫾ 30.0 mm Hg (P < 0.0001) and 20.2 ⫾ 22.1 mm Hg (P = 0.025) (instep), and 13.8 ⫾ 19.3 mm Hg (P < 0.0001) and 9.2 ⫾ 16.3 mm Hg (P = 0.041) (sole), respectively. Changes of KDQOL score showed significantly better result in the role of physical score in Group A compared with Group B. Although heart rate was unchanged in Group A, 9.3/min increase was seen in Group B patients who received cilostazol. There was no intergroup difference in cardiovascular events and/or PAD events between the two groups during the study period. This exploratory pilot study suggested BPS was as effective as anti-platelet drugs in improving microcirculation in HD patients. Key Words: Beraprost sodium, Hemodialysis, Kidney disease quality of life, Peripheral arterial disease, Skin perfusion pressure.
Peripheral arterial disease (PAD) is common (1,2), and has a significant impact on mortality in patients on HD (3). Once they undergo a major amputation of a lower limb due to PAD, the 1-year survival rate falls to almost 50% (4), and it is almost comparable to the 1-year survival rate after acute myocardial infarction (AMI) in HD patients (5). Therefore, it is very important to diagnose and treat PAD in HD patients with effective drugs before they develop symptoms of critical limb ischemia (CLI).
Inter-Society Consensus for the Management of PAD (Trans-Atlantic Inter-Society Consensus II: TASCII) recommends the PAD drug cilostazol and serotonin type 2 inhibitor naftidrofuryl because they have evidence-based clinical utility in claudication (6). Cilostazol may be recommended for the treatment of PAD in HD patients as well as in the general population. However, use of cilostazol is contraindicated for patients with congestive heart failure (CHF). HD patients face the potential risk of having CHF by ischemic heart disease, valvular disease, or volume overload. Therefore, great care must be exercised when cilostazol is selected for the treatment of PAD in HD patients. As for naftidrofuryl, it is not approved for use in Japan. Instead of naftidrofuryl, sarpogrelate is used as a PAD drug with similar
Received December 2012; revised January 2013. Address correspondence and reprint requests to Dr Takayasu Ohtake, Department of Nephrology, Immunology, and Vascular Medicine, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura 247-8533, Japan. Email: [email protected]
1
2
T Ohtake et al.
pharmaceutical action as naftidrofuryl, and sarpogrelate has been reported to have a beneficial effect for intermittent claudication (7). Beraprost sodium (BPS) is an oral active prostaglandin I2 analog with several beneficial actions including anti-platelet effects, vasodilation, inhibitory effect of vascular smooth muscle cell growth, and protective effect on vascular endothelial cells (8–10). However, BPS is not recommended in TASC II as a drug for PAD because it has not yet reached final consensus. While there was a negative trial in the USA (11), there was a positive trial in Europe (12). Large randomized interventional studies for the treatment of PAD have been accumulating in the general population. However, they are still lacking in a HD population. Therefore, our purpose in this study was to clarify the efficacy and safety of BPS in HD patients with PAD with a multicenter randomized prospective open-label interventional pilot study (Japanese Peripheral Arterial Disease study in patients with chronic hemoDialysis: J-PADD). PATIENTS AND METHODS Patients and study protocol This study was performed in accordance with the Declaration of Helsinki. Eligible patients were asked about symptoms of PAD including chillness, numbness, ischemic claudication, and resting pain. Previous histories of intervention (percutaneous peripheral intervention or bypass surgery) or amputation due to PAD were also registered. All patients then underwent physiological examination about skin color, warmth, pulse exam of femoral artery, popliteal artery, dorsal artery, posterior tibial artery, and skin lesions, including ulcers and gangrene. This symptomatic information, previous histories of intervention or amputation, and physiological examinations including ankle-brachial pressure index (ABI), toebrachial pressure index (TBI), and skin perfusion pressure (SPP) were basically used to assign a limb ischemia according to the PAD severity classification criteria set by Fontaine et al. (13) When patients fulfilled any ischemic symptoms with at least one abnormality among ABI < 0.9, TBI < 0.6, SPP < 50 mm Hg, or had apparent previous history of intervention or amputation of lower limbs, they were defined as having PAD. Eligible subjects must fulfill all three inclusion criteria for this study, that is, (i) HD patient with PAD (Fontaine classification I–IV) (13), (ii) levels of SPP of instep or sole
