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Suboptimal Treatment of Risk Factors for Atherosclerosis in Critical Limb Ischemia

Posted on: Wednesday, 10 August 2005, 03:01 CDT

Aim. The epidemiology of critical limb ischemia (CLI) is insufficiently studied, and treatment of risk factors for atherosclerosis has received less attention in CLI patients than in patients with coronary or precerebral atherosclerosis. The aim of this study was to establish the incidence of CLI and the quality of risk factor treatment in Swedish CLI patients.

Methods. During 14 months, 316 consecutive CLI patients were referred to the Malmo Department of Vascular Diseases. Two hundred and fifty-nine (82%) consented to evaluation of intercurrent disease, medication, ankle and arm blood pressures (BP), plasma glucose and lipid levels, phomocysteine, cardiolipin antibodies and activated protein C (APC)-resistance.

Results. The incidence of CLI was 38/100 000 inhabitants/year. Patient age was 7510 years, and BP 14726/7514 mmHg. Systolic or diastolic BP above recommended levels (140/90 mmHg) occurred in 137 (53%) patients. P-cholesterol was 4.81.2 mMol/L, but cholesterol above recommended level (5 mMol/L) or LDL above recommended level (3 mMol/L) occurred in 125 (48%) patients. Only 24% of patients met national recommendations for both BP and lipid levels. Diabetes mellitus was previously known in 123 (47%) patients, and another 12 (5%) patients showed diabetic fasting glucose levels during the hospital stay. Eighty-four (32%) patients were active, and 72 (28%) were former smokers. Myocardial infarction or angina pectoris had previously been diagnosed in 123 (47%) patients. P-homocysteine was 177 _mol/l, cardiolipin antibodies occurred in 71 (27%) and APC- resistance in 34 (13%) patients.

Conclusion. Patients with CLI show high comorbidity in vascular diseases and high prevalence of modifiable risk factors for atherosclerotic vascular disease. The use of evidence-based medical therapy is suboptimal in this high-risk group.

[Int Angiol 2005;24:59-63]

Key words: Risk factors - Limb - Ischemia.

Critical leg ischemia (CLI) is clinically defined as chronic ischemic rest pain, ulcers, or gangrene attributable to objectively proven arterial occlusive disease.1 For scientific purposes, the definition also includes an ankle pressure of <50-70 mmHg or toe pressure of <30-50 mmHg.1 Patients with CLI represent about 1% of the total number of patients with peripheral vascular disease (PVD).1 Several studies have demonstrated that patients with PVD have a 3- to 5-fold increased risk of cardiovascular mortality compared with age-matched controls,2-4 and patients with CLI have a 1-year mortality of 20%.5, 6 Furthermore, patients with PVD often have extensive coronary artery disease. Coronary arteriosclerosis is present in 90% of patients undergoing routine coronary angiography before elective peripheral vascular surgery,7 and these patients have a 30-day mortality of 5-6% after major vascular surgery.8 Although optimal treatment of risk factors for atherosclerosis has in an observational study been shown to improve the prognosis of patients with PVD,9 recent studies have demonstrated that risk factors for arteriosclerosis are often suboptimally treated in this group of patients.9,10

The aim of this study was to evaluate the incidence of CLI, and the occurrence of risk factors for atherosclerosis and their treatment among patients with CLI in a Swedish in-hospital population.

Materials and methods

Subjects

The Department of Vascular Diseases at Malm University Hospital is the single referral center for all CLI patients in the 3 southernmost health care districts in Sweden (723 750 inhabitants in the year 2001). During a 14-month period, 316 patients were referred to the Department of Vascular Diseases with a confirmed diagnosis of CLI. Two hundred and fifty-nine patients (82%) consented to the present study. The diagnosis of CLI was made in accordance with TASC scientific criteria.1 In those cases where arteries in the affected leg were non-compressible and ankle pressure was >50-70 mmHg,1 the diagnosis was confirmed by an experienced consultant in vascular surgery and by measurements of toe pressures.

TABLE I.-Characteristics of 259 patients with chronic critical limb ischemia. Values are meanSD or n (%).

Laboratory analyses

Venous blood glucose was determined by a routine hexokinase method. P-triglycerides and ptotal-cholesterol, LDL-and HDL- cholesterol were determined on a DAX 48 automatic analyzer with the use of reagents and calibrators from the supplier of the instrument (Bayer AB, Gothenburg, Sweden).11

Plasma homocysteine was analyzed by a highperformance liquid chromatographic assay.12-14 The reference values were below 18 Mol/ L and the interassay coefficient of variation was 3.7%. We tested resistance to activated protein C (APC) with predilution of sample plasma in factor V deficient plasma, CV was 7%. The method 15 has a specificity and sensitivity of near 100% for the factor V:Q^sup 506^ allele, which is the mutation responsible for APC resistance with so- called low APC ratio.

Anticardiolipin antibodies were evaluated in serum by ELISA.16 The reference values were <20 GPLU, and values >40 GPLU were considered positive.

Statistics

All variables were recorded in a database, and statistical analysis and calculations, were performed using the statistical software Stat View 5.0 (SAS Institute, Cary, NC, USA). Results are presented as meanSD or n. (%).

TABLE II.-Risk factors for atherosclerosis in 259 patients with critical limb ischemia. Hypertension was defined as antihypertensive medication, or systolic blood pressure (BP) >140 mmHg, or diastolic mood pressure >90 mmHg. Hyperlipidemia was defined as lipid- lowering medication, or p-cholesterol >5 mmol/l, or p-LDL- cholesterol >3 mmol/l. Va. Values are meanSD or n (%).

Results

The incidence of CLI in our population was 38/100 000 inhabitants/ year. Patient age was 7510 years, and blood pressure (BP) 14726/ 7514 mmHg. Systolic or diastolic BP above recommended levels (140/ 90 mmHg) was seen in 137 (53%) patients. P-cholesterol was 4.81.2 mMol/L, but cholesterol above recommended level (5 mMol/L) or LDL above recommended level (3 mMol/L) occurred in 125 (48%) patients. Only 62 (24%) of patients showed both BP < 140/90 and total and LDL cholesterol <5 and 3 mMol/L, respectively. Diabetes mellitus was known at presentation in 123 (47%) patients, and another 12 (5%) patients showed diabetic fasting glucose levels during the hospital stay. Eighty-four (32%) of patients were active smokers, and another 72 (28%) were former smokers. Ischemic heart dis ease (previous myocardial infarction or angina pectoris) had been diagnosed in 123 (47%) patients. P-homocysteine was 177 Mol/L, positive test for cardiolipin antibodies occurred in 71 (27%) and APC-resistance in 34 (13%) patients. One hundred and eighty (69%) patients were on platelet inhibitors, and another 32 (12%) on oral anticoagulants. Ninety-seven patients (37%) were on ACE-inhibitor or angiotensin II receptor-blockers, whereas lipid-lowering therapy had been prescribed to 61 (24%) patients (Tables I, II).

Discussion

The incidence of CLI in Southern Sweden was comparable to previously reported figures from other countries of 30-50/100 000 inhabitants per year.1, 17, 18 Our study also confirmed that patients with CLI showed a high prevalence of risk factors for atherosclerotic disease associated with increased mortality and severity of lower limb ischemia.9, 10 In spite of almost all our patients having been controlled and treated by different physicians prior to hospitalization for CLI, only 24% of patients met current national recommendations for blood pressure and lipid levels. This proportion would have been even smaller if lower blood pressure limits had been used for diabetic patients.

Diabetes mellitus was known at presentation in 47% of our CLI patients, and newly detected during admission in another 5%. Diabetes mellitus is an important risk factor for large vessel arteriosclerosis, and also affects the prognosis. Progression of CLI to gangrene develops in 40% of diabetic CLI patients compared with 9% of nondiabetic CLI patients 19 and major amputations are 11 times more frequent in diabetic PVD patients than in nondiabetic PVD patients.20 Intensive glycemic control decrease microvascular diabetic complications but had no effect on the risk of death or amputation due to PVD in the United Kingdom Prospective Diabetes Study of type 2 diabetic patients.21

Hyperlipidemia occurred in 64% of patients in our study. Plasma levels of total- and low-density lipoprotein (LDL) cholesterol are important risk factors for coronary heart disease,22 and statins have beneficial effects on plaque stabilization, platelet adhesion, thrombosis, inflammation and endothelial function.23 Although lipid reduction has received less attention in PVD than in coronary heart disease, there are several indications of beneficial effects. The Program On the Surgical Control of Hyperlipidemias (POSCH) study,24 in which a 38% reduction in LDL cholesterol was obtained by partial ileal bypass, reported a reduction in PVD and intermittent claudication after 10 years follow-up. In the Scandinavian Simvastatin Survival Study25 patients with ischemic heart disease treated with simvastatin showed a 38% risk reduction for new or worsening intermittent claudication. Although pravastatin does not affect femoral atherosclerosis in primary prevention, it signif\icantly reduced the intima-media thickness of the common femoral artery in subjects with coronary artery disease.26 In the Heart Protection Study 27 with simvastatin in 20 536 patients, out of which 2 701 had PVD, LDL-cholesterol reduction was associated with a significant mortality reduction also in the subgroup with PVD. Although there is good evidence supporting statin treatment among patients with PVD, our study confirmed that lipid-lowering treatment is insufficient 9, 10 also among Swedish CLI patients.

In our study, 53% of patients showed BP above currently recommended levels. The HOT trial 28 showed that patients who reached diastolic BP 82.3 mmHg achieved maximum cardiovascular protection, but achievements of targets for BP controls (<140/90 mmHg) are low even in specialist centers. In our study 37% of patients were on ACE or angiotensin II inhibitors which may have further protective effects against cardiovascular events in PVD patients. In the Heart Outcome Prevention Evaluation Study,29 44% of patients randomized to ramipril 10 mg or placebo for 4-6 years had PVD, and the efficacy of ramipril regarding reduction in the vascular death, myocardial infarction, or stroke was similar when compared with those without PVD.

In our study 32% of patients were active smokers and another 28% were former smokers. Cigarette smoking is a most powerful risk factor associated with the etiology and clinical progression of PVD,1, 30 and increases the risk of amputation and reduces the chance of successful surgical revascularization.31 Smoking cessation in PVD patients slows the progression to CLI and reduces the risks of vascular death.32

Antiplatelet or oral anticoagulant therapy was prescribed to over 80% of our patients at admission for CLI. In contrast to our data on lipid and blood-pressure lowering drugs this figure must be considered as satisfying, as it is considerably higher than among Swedish patients presenting with acute myocardial infarction.33 Antiplatelet agents are known to reduce the risk of vascular death, myocardial infarction, and stroke by approximately 25% among patients with PVD.34, 35 Furthermore, aspirin therapy significantly improves vascular-graft patency after peripheral bypass surgery or angioplasty.36 In the CAPRIE study 37 clopidogrel conferred an 8.7% further relative risk reduction for stroke, myocardial infarction, or vascular death compared with aspirin among patients with myocardial infarction, ischemic stroke or PVD. Even though relative risk reduction with clopidogrel was greater among PVD patients than among patients with myocardial infarction or stroke, current recommendations38 still consider aspirin as first-line antiplatelet treatment in PVD.

Increased homocysteine levels were seen in 37% of our patients. There is a more substantial relation between hyperhomocysteinemia and peripheral atherosclerosis compared to atherosclerosis in the coronary arteries.39 In addition, the rate of progression of intermittent claudication is associated with plasma homocysteine levels.40 Homocysteine levels can be lowered by folate treatment,39 whether this influences prognosis in PVD patients is not known, however, and recommendations can therefore not be made.

Cardiolipin antibodies were found in 27% of patients in our study compared to 1-5% in healthy individuals.41 Whether this high prevalence is related to survival or graft occlusion will be evident from future follow-up. Long-time warfarin treatment is recommended in-patients with venous thromboembolism and persistent cardiolipin antibodies,42 but whether warfarin also should be considered in CLI patients with cardiolipin antibodies is not known. Furthermore, a recent metaanalysis has shown that anticardiolipin antibodies are weaker risk factors than lupus anticoagulants for thrombosis than in the antiphospholipid syndrome.43 Apart from its associations with venous thromboembolism,44 APC-resistance has been proposed to be associated also with peripheral arterial vascular disease.45 As this has recently been challenged,46 however, the potential significance of the prevalence of 13% of APC-resistance in our patients cannot be established.

Conclusions

Risk factors for arteriosclerosis are common among patients with CLI. However, the intensity of life style modification and use of evidence-based medical therapy was suboptimal in these high-risk patients. Patients with PVD and CLI need to be evaluated and treated by physicians with knowledge about and interest for treatment of risk factors for arteriosclerosis.

Acknowledgements.-We thank Barbro Palmqvist and Pehr Ahlquist for their skillful technical assistance.

Part of this work was presented as an abstract at the European Chapter Congress or the International Union of Angiology, Toulouse, France, October 7-11, 2003.

This study was supported by grants from the Ernhold Lundstrm Foundation, Research Funds at University Hospital MAS, the Albeit Phlsson Foundation, and the Hulda Ahlmrolh Foundation.

Received November 10, 2004. Accepted for publication December 29, 2004.

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J. BARANI, I. MATTIASSON, B. LINDBLAD, A. GOTTSATER

Department of Vascular Diseases, University of Lund, Malm University Hospital, Malm, Sweden

Address reprint requests to: J. Barani, University of Lund, Department of Vascular Diseases, Malmo University Hospital, S-205 02 Malmo, Sweden. E-mail: jamal.barani@skane.se

Copyright Edizioni Minerva Medica Mar 2005

Source: International Angiology

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