Medical treatment of peripheral arterial disease and claudication

2. Overview Introduction Risk factors Clinical manifestation Modification of risk factors Antiplatelet Rx Exercise Rx for claudication Drug Rx for claudication Conclusion

3. Introduction PAD caused by atherosclerotic occlusion of arteries to legs Prevalence 12% and increases to 20% if persons older than 70 yr. Affects men and women equally pt. with PAD , even absence of Hx of MI or ischemic stroke have same relative risk of death from CVS cause as pt. with Hx of CAD or CVD

4. Introduction Rate of death of all causes equal in men and women and is elevated even in asymptomatic pt. Severity of PAD is closely associated with risk of MI , ischemic stroke , and death from vascular cause Lower ABI � greater risk of CVS events Critical leg ischemia � mortality of 25%

6. Introduction Claudication = walking induced pain in one or both legs [primarily affecting calves] does not go away with continued walking , relieved by rest Present in 15-40% of PAD Associated with diminished ability to perform ADL

7. Risk factors Older age [>40 yr.] Smoking DM Hyperlipidemia HT Hyperhomocysteinemia

8. Clinical manifestations 1/3 have typical claudication In pt. with claudication , severity increases slowly : 25% worsening claudication : 5% undergo amputation within 5 yr. : 5-10% have critical leg ischemia [ischemic pain in distal foot , ischemic ulceration , or gangrene]

9. Clinical manifestations > 50% of pt. identified as PAD on ABI do not have typical claudication , but have other types of leg pain on exertion � with reduced activity and quality of life

11. Modification of risk factors Smoking cessation Rx of hyperlipidemia Rx of DM Rx of HT Additional approach

12. Smoking cessation Slow progression to critical leg ischemia and reduces risk of MI and death from vascular causes Not certain that smoking cessation reduces severity of claudication From meta-analysis : did not improve MWD

13. Rx of hyperlipidemia Statin not only lower serum cholesterol concentration , but can improve endothelial function Lipid-lowering Rx has benefit in PAD , who often coexisting CAD and CVD Target : serum LDL< 100 mg/dl serum TG < 150 mg/dl

14. Rx of DM Intensive control BS prevents microvascular complications , but its effect on macrovascular complications is less certain From UKPDS : intensive drug Rx � trend toward a reduction in MI but had no effect on amputation due to PAD Intensive BS control in type 1,2 DM � may not favorably affect PAD

15. Rx of HT Data are not available to clarify whether Rx will alter progression of disease or risk of claudication BB : from meta-analysis , BB are safe in pt. with PAD , except in most severe affected pt. ACEI , from HOPE : death from vascular causes , nonfatal MI or stroke did not differ significantly between pt. with PAD and no PAD

16. Additional approach High serum homocysteine = independent risk factor for PAD and increases risk of death from CVS causes B vitamins and folate lower serum homocysteine concentration Despite ease of Rx , no clinical trials demonstrating benefit in pt. with PAD

17. Additional approach Estrogen Rx reduces several CVS risk factors in postmenopausal women Estrogen has no role in Rx of PAD in postmenopausal women Presence of PAD is not contraindication to estrogen Rx in women with indication Estrogen has been associated with reduce graft patency in women undergo femoropopliteal bypass Sx

18. Antiplatelet Rx In pt. with cardiovascular disease : antiplatelet reduce risks of nonfatal MI , ischemic stroke and death from vascular causes Support use of antiplatelet in pt. with PAD

19. ASA FDA expert panel found insufficient evidence to approve ASA as indicated for pt. with PAD ASA may favorably affect peripheral circulation : from Physicians� Health Study [1st prevention trial] , ASA reduced subsequent need for peripheral arterial Sx

20. ASA High dose ASA [600-1500 mg/d] as effective as low dose ASA [75-325 mg/d] ASA alone as effective as combination of ASA and dipyridamole , sulfinpyrazone or ticlopidine in prevent graft occlusion

21. Ticlopidine [Ticlid] In PAD , ticlopidine more effective than placebo in reducing risk of fatal or nonfatal MI or stroke Ticlopidine may reduce severity of claudication and need for vascular Sx Risk of thrombocytopenia , neutropenia [2.3%] and TTP [1:2000-4000]

22. Clopidogrel [Plavix] Fewer hematologic side effects than ticlopidine FDA approval clopidogrel for 2nd prevention of atherosclerotic events in pt. with atherosclerosis , include PAD Report of TTP = 4:1000000

23. Summary for antiplatelet drug Although data are not conclusive , ASA should be considered 1st antiplatelet drug for preventing ischemic events in PAD ASA also effective in maintain vascular graft patency and may prevent thrombotic complications of PAD FDA approval clopidogrel for prevent ischemic events in PAD and may be more effective than ASA

24. Exercise Rx for claudication Demonstrated in > 20 randomized trials : exercise improves MWD , QOL , and community-based functional capacity Rigorous exercise training program may be as beneficial as bypass Sx and may be more beneficial than angioplasty Meta-analysis , exercise training increased MWD 179 m.

25. Exercise Rx for claudication Greatest improvements in walking ability occurred when each exercise session > 30 min , at least 3 times/wk , pt. walked until near maximal pain was reached and program lasted 6 mo or longer Time course of response to exercise program not been fully established , benefit observed as early as 4 wk

26. Exercise Rx for claudication Exercise improved maximal walking time 150%, exceeded than medication [pentoxifylline 20-25% , cilostazol 40-60%] Several limitations : require a motivated pt. in supervised setting

27. Drug Rx for claudication Vasodilator drugs Pentoxifylline [Trental] Cilostazol [Pletal] Naftidrofuryl [Praxilene] Levocarnitine and propionyl levocarnitine Prostaglandins

28. Vasodilator drugs Papaverine [1st medication studied for claudication] ; no evidence of clinical efficacy of drugs of this class Vasodilators do not affect stenosed/occluded vv. that dilate/constrict due to endogenous factors , but may decreased resistance in other vv. Vasodilators can lower systemic pressure = reduction in perfusion pressure Current data do not support use of vasodilators for claudication

29. Pentoxifylline Methylxanthine derivative that improve deformability of RC and WC , lower plasma fibrinogen concentration and has antiplatelet effect Meta-analysis : net benefit 44 m. in MWD , may have small effect on walking ability , insufficient to support its widespread use

30. Cilostazol FDA approved in 1999 for Rx claudication Inhibit phosphodiesterase type 3 � increase intracellular concentration of c-AMP Inhibits platelet aggregation , formation of arterial thrombi , vascular smooth muscle proliferation and cause vasodilatation Extensive hepatic metabolism : CYP3A4 , drug that inhibit CYP3A4 may increase serum cilostazol concentrations

31. Cilostazol 4 RCT : improve both pain free and MWD , compared with placebo 3 RCT : improve several aspects of physical functioning and QOL Causes small increase in ABI and serum HDL concentration Side effect : headache [34%] , transient diarrhea , palpitation and dizziness

32. Cilostazol Can be administered with ASA , no data on safety of coadministration of cilostazol with clopidogrel Cilostazol should not be given to pt. with claudication who also have HF

33. Naftidrofuryl Antagonism of 5-hydroxytryptamine receptors Improve pain free but not MWD Not available in USA

34. Levocarnitine and propionyl levocarnitine In PAD : metabolic abnormalities develop in skeletal muscles [impairment of activity of mitochondrial electron transport chain in ischemic muscle and accumulation of intermediates of oxidative metabolism =acylcarnitine] Claudication caused not just by reduced blood flow but also by metabolism alteration

35. Levocarnitine and propionyl levocarnitine Drug may improve metabolism and exercise performance of ischemic muscle Improve MWD and QOL Not been approved for use in USA

36. Prostaglandins Evaluated primarily for Rx critical leg ischemia , but fewer studies in claudication PGE1 and beraprost improve MWD and QOL Side effect : headache , flushing and GI intolerance Use of PG in PAD need further evaluation

37. Conclusion PAD should be considered candidate for 2nd prevention strategies , just as CAD Antiplatelet : effective in reduce risk of fatal and nonfatal ischemic events in PAD ASA should be considered in all pt. , with clopidogrel an alternative [potentially more effective drug]

38. Conclusion Walking-based exercise program considered first for all pt. with claudication Cilostazol improve both pain free ,MWD and QOL

39. When should a pt. be referred to a vascular surgeon ? Pt. has unacceptable symptoms despite appropriate Rx Pt. has weak or absent femoral pulse Pt. with critical limb ischemia [rest pain , gangrene , or ulceration] should be referred urgently

40. Available drug in Siriraj Hospital

41. References Medical treatment of peripheral arterial disease and claudication : NEJM Vol.344 , No.21 , May 2001 Exercise training for claudication : NEJM Vol.347 , No.24 , December 2002 Management of peripheral arterial disease in primary care : BMJ Vol.326 , March 2003 Diabetes and vascular disease : Circulation 2003;108:1655-1661 Secondary prevention of peripheral vascular disease : BMJ Vol.320 , May 2000