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CHROINC ISCHEMIA

Medical management &Decision makingMohammed salah

introduction

Patients with lower extremity ischemia are typically divided a into two groups—

1 -intermittent claudication 2 -critical Limb ischemia (CLI)

Claudication and CLI are managed differently because of major differences in their

natural histories and expected clinical outcomes after treatment .

in general, there is more consensus among clinician regarding decision making for CLI because the natural history of untreated CLI more frequently leads to limb loss than does claudication.

. Patients with CLI often have severe associated cardiovascular comorbidities and are generally older and in poorer health than those with claudication.

Treatment must therefore be structured accordingly. In contrast, patients with claudication typically seek treatment for the relief of lifestyle limiting pain with ambulation.

In general, there is more consensus among clinician regarding decision making for CLI because the natural history untreated CLI more frequently leads to limb loss than does claudication.

Because atherosclerosis is a systemic disease, the initial treatment of lower extremity PAD should include risk fact modification in an effort to limit progression of the atherosclerotic process.

Pharmacologic treatment is directed toward The relief Of symptoms and The stabilization of Existing atherosclerosis is also essential.

Patients presenting with PAD are at significantly increased risk for premature cardiovascular events, including myocardial infarction (MI), stroke, and death. Detection of occult PAD is an important marker for systemic atherosclerosis

Any patient older than 40 years who has an ankle-brachial index (ABI) of less than 0.90 has significant PAD, even in the absence of symptoms.

An ABI of less than 0.90 is 95% sensitive in identifying angiographically confirmed PAD . Interestingly, more than 50% of patient with an abnormal ABI fail To show typical symptoms Of claudication or CLI because of the coexistence of other major comorbidities, a condition sometimes referred to as “chronic subclinical lower extremity ischemia.”

Treatment:RISK FACTOR MODIFICATION:

Smoking CessationRigorous BSL control

BP reductionLipid Lowering Therapy

MEDICAL MANAGEMENT:Antiplatelet therapy e.g. Aspirin/Clopidogrel Phosphodiesterase Inhibitor e.g. Cilostazol Foot Care

EXERCISE:Claudication exercise rehabilitation program 30-45mins 3x weekly for 12 weeks

Smoking

. Smoking cessation has been shown to reduce the risk of MI and death in patients with PAD and to delay the progression of lower extremity symptoms from claudication to CLI and limb loss.

Nicotine inhalation has been demonstrated to1- reduce high density lipoprotein (HDL) levels,2- increase platelet aggregation,3- decrease prostacyclin, increase levels of thromboxane, and promote vasoconstriction. Each of these effects contributes to the development and progression of atherosclerotic process.

BENEFITS OF SMOKING CESSATIN

Beneficial effects of smoking cessation 1- improvement in claudication, 2- modest improvement in the ankle-brachial index, 3- reduction in the likelihood of amputation. 4- improvement in the patency rates of arterial bypass grafts 5- improvement in overall survival.

The importance of smoking cessation extends to patients who have undergone lower extremity revascularization because there is a threefold increased risk of graft failure in smokers compared with nonsmokers

The role of the physician is to educate patients about the consequences of this high-risk behavior, provide emotional support, and prescribe pharmacologic aids aimed at treating the addiction

SUMMERY OF SMOKING CESSATION therapyNRT buccal mucosa spray patch

1ST LINE DRUGS bupropion varenicline

2ND LINE nortriptyline clonidine

EMERGING THERAPY nicotine vaccine NIXCVAX

Contraindication to NRTActive smoking Pregnancy lactation Post MI Burger disease can be replaced by

pharmacotherapy Worsen angina pectoris pain Severe arrythmiaSide effect nausea, constipation ,GIT irritation

headache, insomnia ,irritability ,arrhythmia up to AF

Pharmacotherapy The addition of pharmacologic agents, such as bupropion, have increased smoking cessation rates in randomized studies of patients with PAD More recently, varenicline (Chantix, Pfizer Inc., New York, NY) has been approved for use in the United States, with remarkable early results. This pharmacologic agent acts as a partial agonist of the α 4 β 2 nicotine acetylcholine receptor and was developed for the sole purpose of treating tobacco addiction.

Diabetes MellitusThe association between DM and atherosclerotic vascular disease is well documented.

Diabetes is widely prevalent among patients with lower extremity ischemia. It has been estimated that each incremental 1% increase in glycosylated hemoglobin is associated with a 28% increase in risk for PAD. 1- Alterations in nitric oxide availability to endothelial cells and the2- stimulation of proatherogenic activity in vascular smooth muscle cells by the reduction of phosphatidylinositol-3 kinase. 3- enhanced platelet aggregation, 4- increased blood viscosity, and elevation of fibrinogen levels .

Effect of hypertension on atheroscelorsis

Most patients require multiple agents for adequate blood pressure control. Angiotensin-converting enzyme (ACE) inhibitors are particularly beneficial, as shown in the Heart Outcomes Prevention Evaluation (HOPE) study.

Patients with adequate blood pressure control using the ACE inhibitor, ramipril, experienced a reduction in subsequent stroke, MI, and vascular-related mortality.)

ACE inhibitors approved as a cardioprotective drug in high risk patient.

The target BP level is 140\90 in non DM patient 130\80 in DM or patient with chronic renal insufficiency .

Target of therapy

HYPERLIPIDEMIATotal serum cholesterol levels greater than 200 mg/dL (5.18 mmol/L) are associated with an increased risk of cardiac-related events, especially in combination with a low HDL fraction (<40 mg/Dl) .

Lipid lowering agents, specifically 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (“statins”), have been shown to decrease the risk of MI-related death in high-risk patients.

Improvements in leg function, ABI, walking performance, symptoms of claudication, and perioperative and long-term mortality have been demonstrated

HYPERLIPIDEMIA The beneficial effects of statin therapy are:-pleomorphic , independent of their lipid lowering properties;

- altering the lipid content of platelets, thereby decreasing platelet aggregability

- stabilizing existing atherosclerotic plaques,

- decreasing oxidative stress,

-reducing vascular inflammation.

HomocystenemiaThe important influence of homocysteine metabolism on

premature atherosclerosis was suspected in the 1990s when distinct group of young patients with advanced atherosclerosis and no other established risk factors was investigated.

Plasma levels of homocysteine are regulated in part by B vitamins, and vitamin supplementation lowers plasma homocysteine levels.

Thus, low levels of folate and vitamin B are also associated with the risk of PAD, perhaps through the modulation of homocysteine levels.

Early studies found elevated homocysteine to be an independent risk factor for coronary artery disease and stroke.

Homocysteinemia

- Elevated circulating homocysteine results in1- endothelial dysfunction and injury, 2-followed by platelet activation and thrombus formation.3- production of hydrogen peroxide (which mediates endothelial injury), 4- increases in factors XII and V, decreases in protein C, and 5- inhibition of thrombomodulin and heparin sulfate.

Homocystenemiaserologic evaluation for elevated homocysteine levels is still recommended for patients with:

1- family histories of multiple thrombotic events, 2- premature cardiovascular symptoms in the absence of conventional risk factors, and 3- coronary artery disease, PAD, stroke, deep venous thrombosis, and pulmonary embolism.

- Supplemental B vitamins or folic acid therapy may be worthwhile.

TREATMENT 1- VASODILATORS 2- ANTIPLATELET3- EXERCISE THERPHY 4-IPC

EXERCISE THERAPYMultiple reports have clearly demonstrated improvements in pain-free ambulation and overall walking performance with Data from more than 20 randomized trials have confirmed that exercise therapy is the best initial treatment of intermittent claudication.

The benefits Of Exercise Extend Beyond improvement In The symptoms Of claudication. Regular aerobic exercise reduces cardiovascular Risk By Lowering Cholesterol And Blood Pressure And By Improving glycemic control.

structured exercise The guidelines suggest that exercise training, In The Form Of walking, Should Be Performed For a minimum of 30 to 45 minutes per session, three to four times per week, for a period not less than 12 weeks.

EXERCISE THERAPYDuring each session, the patient should be encouraged

to walk until the limit of lower extremity pain tolerance is reached, followed By A short period of rest until pain relief is obtained, then a return to exercise.

This cycle should be followed for the duration of the session.

Although exercise therapy appears to be easy to implement, Effectiveness Is often limited by poor patient compliance. Studies have shown the superiority of clinic-based exercise programs over home-based programs.

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antiplateletsThere is convincing evidence that antiplatelet agents such as aspirin and clopidogrel are effective in preventing cardiac and stroke events in patients with PAD.it is therefore recommended that an antiplatelet drug should be prescribed for these patients unless there is a clear contraindication to such therapy.Antiplatelet therapy is now widely accepted among physicians For the treatment of cardiovascular disease, and it has been shown to reduce the risk of nonfatal MI, ischemic stroke, and vascular-related death. It should be used in all patients with Clopidogrel (Plavix, Bristol-Myers Squibb, New York, NY) is the only antiplatelet agent approved by the FDA for the secondary prevention of atherosclerotic vascular disease, including PAD Dual antiplatelet has no role in prevention of CVD in PAD . Associated with increase risk of bleeding .pictomaide is prevent stroke in DM pt more efficient than aspirin .

pentoxifylline (Trental, sanofi-aventis, Paris, France) the first drug approved by the FDA for the treatment of intermittent claudication.

Mechanism of action

It is a methylxanthine derivative that is thought to improve oxygen delivery because of its rheolytic effect on red blood cell wall flexibility and deformability, ultimately reducing blood viscosity .

Pentoxifylline is also believed to inhibit platelet aggregation and to increase fibrinogen levels.

PENTOXFYILLINE

Pentoxifylline is well tolerated, safe, and relatively inexpensive. Although its clinical impact has been modest, pentoxifylline represents one of the earliest successful pharmacologic advances for The Treatment Of claudication.

Dosing recommendations For pentoxifylline begin at 400 mg orally three times daily and can be increased as tolerated up to 1800 mg/day.

Pentoxifylline can interfere with blood clotting, Especially If Taken withSodium warfarin. Pentoxifylline Has rarely been associated with nausea, headache, anxiety, insomnia, drowsiness, and loss of appetite. Increased blood pressure can occur, so blood pressure should be monitored

Cilostazol

Cilostazol (Pletal, Otsuka Pharmaceutical Ltd., Tokyo, Japan) gained FDA approval in 1999 for the treatment of intermittent claudication.Mechism of actionphosphodiesterase III inhibitor increases cyclic adenosine monophosphate (cAMP) And Results In A Variety Of Physiologic effects, Including the inhibition of smooth muscle cell contraction and platelet aggregation. Cilostazol is also thought to decrease smooth muscle cell proliferation, a process that has been implicated in coronary artery restenosis after percutaneous transluminal angioplasty. Finally, cilostazol has a beneficial effect on plasma lipid concentrations, resulting in a decrease in serum triglycerides and an increase in HDL. There is also increasing evidence that cilostazol may modulate the synthesis of vascular endothelial growth factor (VEGF), potentially stimulating angiogenesis in patients with chronic lower extremity ischemia claudication is unknown, it is likely a combination of these effects.

Cilostazol has a moderate but notable adverse effect profilethat includes headache, diarrhea, and gastrointestinal discomfort. Its use is contraindicated in patients with Congestive heart failure, and high plasma drug levels may result when taken in combination with other medications metabolized by the liver via the cytochrome-P450 pathway.

The adverse effects of cilostazol can be minimized by initiatingA progressiveTreatment regimen, Starting At 50 mg/day for 1 week, increasing to 50 mg twice daily the following week, and finally achieving the standard dose of 100 mg twice daily in week 3. Of the pharmacologic agents used to treat claudication, cilostazol has the most use. data supporting its clinical

NaftidrofurylMechanism of action

Naftidrofuryl is a serotonin antagonist thought to improve aerobic metabolism in ischemic tissue by stimulating the entry of carbohydrate and fat into the Krebs cycle at the mitochondrial level, as well as by promoting peripheral vasodilatation. Studies have documented increased tissue oxygenation, increased ADP levels, and reduced lactic acid.

It has been widely available in Europe for the treatment of claudication for more than 20 years. Several trials have demonstrated a clinical benefit ranging from 15% to 100% improvement in pain-free walking distance, but with no significant effect on maximal walking distance.The primary adverse effects of naftidrofuryl include minor gastrointestinal symptoms, flatulence, and abdominal discomfort. Naftidrofuryl is not currently approved for use in the United StatesThe recommended maximum dose is 200 mg three times a day..

. Intermittent Pneumatic Compression forPeripheral Artery DiseasIntermittent pneumatic compression (IPC) in combination with appropriate risk factor modification may be a viable method of treatment for patients with unreconstructable vascular disease, for those who are physiologically unfit for surgical intervention, or for patients with

intermittent claudication Who Do Not Want Invasive treatment .

IPC involves sequential Inflation and deflation Of pneumatic pressure cuffs positioned at the foot or calf. Inflation-deflation rates vary according to the system used, each applying a pressure up to 120 mm Hg for 2 to 3 seconds before deflating. This sequence is continued at a rate of three cycles per minute throughout the treatment session. The physiologic effects of IPC are thought to be a consequence of three mechanisms: an increase in the arteriovenous pressure gradient; reversal of vasomotor paralysis; and enhanced release of nitric oxide

Peripheral arterial disease is a marker of systemic atherosclerosis. Patients with PAD are at high risk for MI and stroke .

Thus, risk factor modification and the prevention of the sequelae of atherosclerosis is the mainstay of therapy .

Patients must be advised to “stop smoking and keep walking.” In addition, antiplatelet therapy (e.g., aspirin) is indicated in all patients with peripheralArterial disease in whom there is no contraindication.

Hypertension must be appropriately treated and diabetes mellitus detected and managed optimally .

The medical management of the symptoms of intermittent claudication should also be addressed If these are significantly impairing the patient’s lifestyle.

Summary

DECISION MAKING FOR REVASCULARIZATION Although the TASC II classification system can be helpful in the revascularization decision making Process (i.e., endovascular or open), atherosclerotic burden as measured by arteriography is not the sole factor upon which treatment decisions should be made.

The TASC classification system lacks any features related to degree of ischemia, wounds, infection, functional status, and conduit availability, all of which are extremely important determinants of revascularization success. Clearly, angiographic anatomy alone cannot guide therapy .

TASC II In January 2000, the TASC for the Management of Peripheral Arterial Disease published a document authored by a working group of representatives from 14 surgical vascular, cardiovascular, and radiologic societies. An updated documen (TASC II) was published in January 2007. Recognizing the importance of the pathologic anatomy for decision making, the TASC working group has classified anatomic patterns of disease involvement (types A through D) for both the aortoiliac and femoropopliteal . segments, based on recommended treatment (endovascular versus open surgery). The TASC working group advocated endovascular treatment for TASC type A lesions and open surgical treatment for TASC type D lesions. For TASC type B and C lesions, the authors concluded that there was insufficient evidence to definitively recommend one modality over the other.

Other Classification

Bollinger Classificationhe Bollinger score, which was used by the BASIL trial, utilizes A Scoring System To Classify Angiographic lesion In Terms of Pattern And severityThere is then an additive component that categorizes severity of lesions into four classes: plaques, stenoses <25%, stenoses <50%, stenoses >50%, or occlusion.

Graziani ClassificationThe Graziani scoring system proposed a new morphologic categorization for disease severity among diabetic patient with CLI. Unlike the Bollinger score, this system described the frequency of various patterns of disease, and correlated angiographic findings with transcutaneous oxygen tensionvalues.

LIMITATION OF TASCIIAnother critical element of decision making focuses on the determination of whether or not a patient will experience a meaningful benefit from a technically successful procedure. Technical success does not always equate directly with clinical success. As a result, it is important to assess baseline functional status and the burden of comorbid conditions. Patients who are either bedridden at baseline or who have prohibitive medical risks may significantly more benefit from a treatment that differs from the TASC II recommendations (based on lesion type alone), to more appropriately balance the chances for functional limb salvage with the risks of periprocedural morbidity. An assessment of the available conduit, if bypass is required, is included in this evaluation. The challenge of decision making in PAD is accurately assessing each of these factors and synthesizing a plan that optimizes The Likelihood Of A Favorable Outcome for Each patient.

LEGS SCORE WIFI CLSS.

LEGS SCOREThe Lower Extremity Grading System (LEGS) was proposed in 2002. The LEGS score is a standardization tool for decisions regarding revascularization strategies for PAD. The LEGS score, which is applicable to patients with either claudication or CLI, can be applied once the decision to intervene has been made., the score considers five objective criteria1—angiographic pattern of disease,2- presenting complaints,3-Functional status of the patient,4-Medical comorbidities,5-and technical factors.to recommend the most appropriate interventional therapy (angioplasty, open surgery, or major limb amputation).

WIFI CLASSIFICATIONcreate a more comprehensive classification system to serve as a more

decision making tool. the SVS Threatened Limb Classification System, incorporates three major

factors that affect amputation rise and clinical management: wound, ischemia, and foot infection (WIfI).

In the SVS WIfI system,1 -wounds are classified from grade 0 to grade 3 based on size, depth, severity,

and anticipated difficulty achieving wound healing .2-Ischemia is classified from grade 0 to grade 4 according to ABI, ankle systolic

pressure, toe systolic pressure, or transcutaneous oximetry .3-Infection is classified from grade 0 to grade 3 based on simple objective

clinical observations .

Traditional treatment recommendations for intermittent claudication have balanced the risk With the goal of preserving Life And limb.

Many Experts Agree That The Best strategy is to initiate systemic medical therapy aimed at reducing cardiac morbidity. This strategy is based on the low relative risk of limb loss in patients with claudication compared with high risk CVD ,stroke.

Cardiovascular Risk Factor Modification And Medical Therapy As the best initial treatment for patients with PAD symptoms limited to intermittent claudication. Revascularization is recommended only in cases of severe disabling claudication or failure of medical ttt.

Medical treatment for intermittent claudication consists of smoking cessation, exercise training, and pharmacologic therapy, as already described .

Ultimately, the selection of the best method of revascularizationFor An Individual With Claudication Is Based On A Balance Between The Risks Of The Specific Intervention And The Degree And Durability Of Improvement That Can Be Expected From The intervention.

.Endovascular therapy is generally preferred to open surgery for most case of claudication .

However, it is important to note that growing body of evidence suggests that the concept that an endovascular option “does not burn any bridges” is false.

long-term patency and success using angioplasty were documented In 1 _focal arterial lesions

2_larg-diameter with good out flow.3 -were more favorable in nondiabetic patients presenting with claudication than in

those with CLI .the common iliac artery, a vessel with all the favorable anatomic characteristics identified by the Atherosclerotic lesions in this segment are usually focal and

possess good outflow. .conversely, long-segment arterial disease, such as a long superficial femoral

artery occlusion, is probably best treated with open bypass .

Critical Limb Ischemia CLI is defined as chronic lower extremity PAD with either ischemic rest pain or the tissue loss (nonhealing ulcers or gangrene).

Typically, symptoms have to be present for more than 2 weeks and associated with an ankle pressure of less than 50 mm Hg or a toe pressure of less than 30 mm Hg.ABI less

than .0,4 .

Decision making for CLI commonly poses three dilemmas:1 -whether to treat medically or with intervention ;

2-if treating with intervention, whether to amputate or revascularize ;3-and if revascularizing, whether to employ endovascular intervention Or Open surgery.

Revascularization is an essential component in the relief of CLI .

1-Although medical adjunctive to revascularization i.e risk factor modification may be important to slow the progression of systemic atherosclerotic disease, they play a secondary role in the treatment of the severely

ischemic limb .2-In those rare cases in which vascular disease is truly

unreconstructable, a trial of intensive wound care, preferably at a dedicated wound care center, may yield satisfactory healing rates for motivated patients with superficial ulcerations, or it may avoid major limb amputation in high-risk patients who are. approaching the end of life

For the majority of patients with CLI, revascularization is the interventional treatment of choice. However, primary limb amputation continues to be required in 10% to 40% of CLI patients because of

1-overwhelming infection 2-unreconstructable vascular disease.

Unreconstructable vascular disease accounts for nearly 60% of patients requiring secondary amputation. In many of these cases, revascularization has failed because of progression of disease, recurrent ischemia, or persistent Infection Or Necrosis Despite A Patent revascularization.

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Patients too sick or infirm to realize the benefit of limb revascularization should undergo palliative primary above knee amputation. However,. Obviously, a non ambulatory, elderly, nursing-home patient with knee contractures and neuropathic heel ulcers would qualify for a palliative above-knee amputation.

limb amputation and prosthetic rehabilitation can be an excellent option, offering an expedient return to a reasonable QoL in selected cases. Maintenance of ambulation can exceed 70%, and maintenance of independence Can exceed 90% in young patient.

For patients who are minimally ambulatory, with multiple comorbidities, the decision is less clear cut. An individualized judgment is required to determine whether these patients will be better served by primary amputation or limb revascularization.

Endovascular Treatment versus Open SurgeryCLI is usually associated with multilevel arterial disease that is not ideally suited to percutaneous intervention. Diffuse, extensive PAD causing CLI in both aortoiliac and femoropopliteal locations and is best treated by surgical bypass according to TASC.However, the primacy of surgical bypass for CLI management has been challenged in recent years and has become the subject of intense debate. Those who favor open surgery for the treatment of CLI often cite superior reconstruction patency and increased durability. However, open surgery is usually associated with higher perioperative morbidity and longer hospitalization. Also, long-term postoperative graft surveillance is necessary to maintain a patent infrainguinal bypass.

cont.hose who favor interventional treatment cite the low morbidity and mortality associated with a procedurethat is usually performed on an outpatient basis.

Although limited reconstruction patency rates associated with endovascular treatment, especially for the high-risk lesions often encountered in CLI, they arguethat restenosis rarely jeopardizes subsequent surgery.

Situational Perfusion EnhancementThey argue that there is a population of asymptomatic patients with subclinical lower extremity ischemia and very low perfusion pressures. These patients become symptomatic only when they develop incidental foot ulceration and do not have the circulatory reserve to heal.

An increase in arterial perfusion, even transiently, usually allows healing of the ulcer. Once the ulcer is healed, maintenance of enhanced perfusion is not critical, and recurrent ischemia is usually well tolerated as the patient resumes the subclinical ischemic state.

When should open surgery be the initial option for CLI?

P.F. Lawrence, A. Chandra EJVES November 2009

Take home message:Parameters for “ open first” revasc. approach:-Anatomical: CFA, infragenicular pop. and

trifurcation-Pathological: extrinsic compression as in pop.

Entrapment, cystic advintitial, exostoses-Physiological: extensive gangrene-Durability: young patients

ANGIOGENESIS FOR PERIPHERAL ARTERIAL DISEASEFor patients with CLI who lack a revascularization option, novel alternative therapies may offer benefit. Angiogenesis is a naturally occurring phenomenon in response to tissue ischemia, and is promoted by proangiogenic factors, including VEGF, fibroblast growth factor, hypoxia-inducible factor-1α, and hepatocyte growth factor.

The concept of therapeutic angiogenesis entails efforts to increase the concentration of proangiogenic factors thereby stimulating growth of new blood vessels from preexisting blood vessels to treat ischemic disease; this may be accomplished by administration of recombinant proteins or gene therapy that induces overexpression of these factors. Therapeutic angiogenesis may also be induced by implantation of endothelial progenitor cells.

angiogenesisThe mechanism by which angiogenesis improves limb perfusion is through the enlargement of collateral blood vessel and possible direct stimulation of wound healing by growth Factor.

Many different growth factors involved in angiogenesis have been individually tested in clinical trials. Because the half-life of the recombinant protein is short, most trials have used gene therapy to allow for a more prolonged expression of the protein. Growth factors that have been studied include various VEGF isoforms, fibroblast growth factor (FGF), hepatocyte growth factor (HGF), and the transcription factor,hypoxia-inducible factor-1α.

Gene therapy has usually been delivered in either a plasmid or an adenovirus via intramuscular injection into the ischemic limb.

Stem Cell TherapyStem cell therapy is another developing technique to induce therapeutic angiogenesis. Autologous stem cell therapies have used bone marrow mononuclear cells or endothelial progenitor cells obtained from bone marrow harvest or, less frequently, from circulating peripheral blood stem cells. Endothelial progenitor cells .can be identified by cell sorting for CD34-positive, VEGF receptor-2–positive cells. Once concentrated, the cells can be injected into the ischemic limb to induce angiogenesis.

injection of bone marrow–derived mononuclear cell injections resulted in a significant increase in ABI and tcPO compared with controls.