Exercise for intermittent claudication

Evaluation of C-Reactive Protein, an Inflammatory Marker, and Infectious Serology as Risk Factors for Coronary Artery Disease and Myocardial Infarction

Effects of probucol and cilostazol alone and in combination on frequency of poststenting restenosis.

Diabetic Foot Ulcers: Prevention, Diagnosis and Classification

Exercise for intermittent claudication

Source: COCHRANE PERIPHERAL VASCULAR DISEASES GROUP

http://som.flinders.edu.au/fusa/cochrane/cochrane/revabstr/ab000990.htm

Objectives: To determine whether, in patients with intermittent claudication, an exercise programme was effective in alleviating symptoms and increasing walking distance. Secondary objectives were to determine whether exercise was effective in preventing deterioration of underlying disease and reducing cardiovascular events.

Search strategy: All publications describing randomised controlled trials of exercise therapy in intermittent claudication were sought using the search strategy described by the Review group on Peripheral Vascular Diseases. This strategy included handsearching of relevant medical journals and extensive MEDLINE searches. In addition, trials were identified by cross-referencing published work, by direct contact with principal investigators of trials, and by EMBASE searches.

Selection criteria: All randomised controlled trials of an exercise regimen versus control, or versus medical or surgical therapy, in patients with intermittent claudication due to atherosclerotic disease were included. The exercise regimen was not specified, and inclusion of trials was not affected by the duration, frequency or intensity of the exercise programme. Possible trials were identified by GCL, and their eligibility for inclusion in the review checked by EE.

Data collection and analysis: Fourteen trials were identified which met the inclusion criteria, but five were subsequently excluded because of poor quality. The remaining nine trials involved a total of just over 200 patients. Five trials compared exercise with an untreated control group (three used placebo tablets), two compared exercise with intervention (surgery and angioplasty), and two small trials used drug regimens as the control (antiplatelets and pentoxifylline). The exercise regimens varied, but all recommended at least two sessions weekly. All trials used a treadmill walking test as one of the outcome measures, six included calf blood flow, and four the ankle brachial pressure index (ABPI). Continuous data were analysed by weighted mean differences, using both the fixed effect and random effects models.

Main results: Exercise therapy significantly improved maximal walking distance (OR 6.51, 95% CI 4.36, 8.66), with an overall improvement in walking ability of approximately 150% (range 74% to 230%). Exercise produced significant improvements in walking distance compared with angioplasty at 6 months (OR 2.17, 95% CI 1.31, 3.03) and antiplatelet therapy (OR 1.06, 95% CI 0.15, 1.97), did not differ significantly from surgical treatment. In one small trial, exercise was less effective than pentoxifylline (OR -0.45, 95% CI -0.66, -0.24). Exercise did not have a significant effect on the ABPI or calf blood flow, and these outcomes were similar after angioplasty or antiplatelet therapy. The ABPI was significantly improved following surgery, however, (OR -0.27, 95% CI -0.37, -0.17), but there was a higher rate of adverse events (18%) and deaths experienced by those undergoing surgery.

Conclusions: Exercise is of significant benefit to patients with intermittent claudication, and therefore should be recommended to all suitable patients. However, further studies are required to determine the longer term benefits of exercise compared with other treatments such as surgery and pentoxifylline, and to evaluate the cost-effectiveness of different exercise regimens.

Evaluation of C-Reactive Protein, an Inflammatory Marker, and Infectious Serology as Risk Factors for Coronary Artery Disease and Myocardial Infarction

Source: J Am Coll Cardiol 1998;32:35-41

It was to test whether C-reactive protein (CRP) and seropositivity to any of three infectious agents are associated with angiographic coronary artery disease (CAD) and clinical myocardial infarction (MI).CRP, an inflammatory marker, is reported to predict risk of MI. The stimulus for CRP is unknown but might include infection. Chlamydia pneumoniae, cytomegalovirus and Helicobacter pylori have been linked to risk of MI or CAD.Blood samples were collected from 363 patients undergoing coronary arteriography and tested for CRP and IgG titers to the infectious agents.CRP was higher in patients with CAD (1.32 mg/dl [SE 0.22, n = 80] vs. 0.58 mg/dl [SE 0.11 mg/dl, n = 109], p = 0.004) and in those with MI (2.05 mg/dl [SE 0.36, n = 47] vs. 0.54 mg/dl [SE 0.08, n = 133], p = 0.0002) than in respective control subjects. Seropositivity for each agent was present in a high proportion of patients with CAD (58% to 77%) or MI (54% to 75%) as well as in control subjects (no CAD: 46% to 74%; no MI: 50% to 77%). However, subjects seropositive to both C. pneumoniae and H. pylori had an increased prevalence of CAD (odds ratio [OR] 2.6, p = 0.02) and MI (OR 2.0, p = 0.15) and tended to have higher CRP levels (1.07 mg/dl [SE 0.16]) than those seronegative to both infectious agents (0.53 mg/dl [SE 0.10], p = 0.06). CRP is elevated in patients with CAD (more than twofold) and in those with MI (fourfold). Infectious serology is highly prevalent in both patients and control subjects. Seropositivity to both C. pneumoniae and H. pylori (but not one agent alone) may predict increased risk and may be associated with higher CRP levels. Infectious serology may be less predictive than previously suggested, but the cause of inflammation in CAD and MI deserves further study.

Discussion:

The study confirmed an association between the inflammatory marker CRP and a history of MI. The association was marked (fourfold elevation) and highly significant (p = 0.0002) but variable and mostly accounted for by a recent MI.

There was an association of CRP to coronary atherostenosis, where a substantial (more than twofold) and significant (p = 0.004) correlation was observed. CRP as an acute phase reactant marker for systemic inflammation is reliably assayed and has been consistently found to be elevated in patients with coronary syndromes. There was an association between CRP and acute ischemia, MI, unstable angina, stable angina, coronary death in smokers.

The independent and prospective value of CRP as a risk factor is most strongly supported by a report from the Physicians Health Study , which found that CRP in the highest quartile was associated with an increased relative risk (2.9) of future MI (p < 0.001). Moreover, baseline CRP elevation was predictive of increased risk during each of 6 years of follow-up. Therapy with aspirin reduced the excess risk. These observations suggest that CRP was marking a chronic, persistent inflammatory state rather than an acute, transient one. In the Physician's Health Substudy , the relation of CRP with severity of CAD itself was not measured, nor was the cause of the inflammatory stimulus for elevated CRP determined.

The possibility that infectious agents may trigger a cascade of biological and biochemical reactions leading to inflammation, atherogenesis and vascular thrombotic events has recently been raised. For CAD, C. pneumoniae and CMV have received the most investigative attention and scientific support. Indeed, H. pylori also has been variably associated with CAD . Other infectious (or noninfectious) causes of inflammation, such as chronic periodontal disease, also might be involved . Evidence for an infectious association with CAD is currently most fully developed for C. pneumoniae.

Conclusions:
The present study confirms the association of elevated CRP levels with a clinical history of MI and extends this association to patients with angiographically documented CAD versus angiographically normal coronary arteries. The association was highly statistically significant, although it showed substantial interindividual variability. The cause of this inflammation was explored by measuring infectious serology for three organisms proposed to play a possible role in atherosclerosis progression: C. pneumoniae, CMV and H. pylori. Seropositivity to each agent was extremely common in patients with CAD (54% to 77%) and also was highly prevalent in age-matched control subjects, indicating a high prevalence of population exposure. Exposure to two agents (i.e., C. pneumoniae and H. pylori) showed associations that deserve further exploration.

The poorer predictive value of individual infectious serologies than previously suggested might be due to an inability to distinguish persistent from resolved infection or because other causes of inflammation are primarily operative. Thus, additional studies investigating infectious factors in CAD and MI and correlating CRP and other markers of inflammation with more specific markers of active infectious and noninfectious causes of inflammation are indicated.

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Effects of probucol and cilostazol alone and in combination on frequency of poststenting restenosis.

Source: Am J Cardiol 1998 Jul 15;82(2):144-147

The present study was conducted to assess the preventive effect of combined treatment with probucol, an antioxidant, and cilostazol, a phosphodiesterase inhibitor, against poststenting restenosis. Study patients were randomized to 4 modality groups 1 week before stenting: control, probucol (500 mg/day), cilostazol (200 mg/day), and probucol plus cilostazol. Treatment on these modalities was conducted from 5 prestent days until the poststenting follow-up evaluation (6 poststenting months). All patients received aspirin (81 mg/day). The efficacy of each modality against restenosis was evaluated in a total 126 patients with 165 coronary arterial lesions, using a quantitative method. The decrease in luminal diameter at the poststenting follow-up was 1.04 +/- 0.57 mm for controls, 0.88 +/- 0.82 mm for those taking probucol, 0.61 +/-0.59 mm for those taking cilostazol (p <0.05 vs control), and 0.40 +/- 0.52 mm (p <0.01 vs control) for the combined treatment group. Restenosis rate per segment was 31.7% for controls, 16.7% for the probucol group, 12.5% for the cilostazol group (p <0.05 vs control), and 9.5% for the combined treatment group (p <0.05 vs the control). Neither mortality, myocardial infarction, stent thrombosis, or coronary bypass surgery, nor any serious complications were observed in the combined treatment group. Combined treatment with probucol and cilostazol has thus proved safe and effective in preventing acute poststenting complications and suppressing chronic restenosis.

Discussion:

It is suggested that probucol may prevent restenosis by exerting an antioxidative effect, suppressing the proliferation of vascular smooth muscle cells. In this study, probucol alone did not significantly suppress poststenting restenosis, probably because treatment with probucol was initiated too late (5 prestent days).

The combined use of probucol with cilostazol would be capable of supplementing the insufficient suppressive effect of probucol from too short a period of administration.

Cilostazol has an action different from ticlopidine as it produces vasodilatation by increasing cyclic adenosine monophosphate in the vascular smooth muscle cells.

It was confirmed that cilostazol has the inhibitory effect of intimal proliferation after coronary angioplasty in humans. This report indicates that cilostazol prevents restenosis after stent implantation.

Adverse reactions to 200 mg/day of cilostazol occurred in 14 patients and 40% of those on cilostazol alone and none of those on the combined treatment had restenosis. This finding suggests that combined treatment may potentially reduce the dose of cilostazol, and that the reduced dose may potentially mitigate adverse reactions to the drug.

Conclusions:

Although the study group was small, the 4 groups appeared to be similar in each demographic factor at baseline. There were few differences in the parameters at baseline between the 4 groups. Neither mortality, MI, stent thrombosis, or coronary bypass surgery, nor any serious complications were observed in the combined treatment group. Combined treatment with probucol and cilostazol has thus proved safe and effective in preventing acute poststenting complications and suppressing chronic restenosis.

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Diabetic Foot Ulcers: Prevention, Diagnosis and Classification

Source: American Family Physician 1998;57(6):1325-1332

Diabetic ulcers are the most common foot injuries leading to lower extremity amputation. Family physicians have a pivotal role in the prevention or early diagnosis of diabetic foot complications. Management of the diabetic foot requires a thorough knowledge of the major risk factors for amputation, frequent routine evaluation and meticulous preventive maintenance. The most common risk factors for ulcer formation include diabetic neuropathy, structural foot deformity and peripheral arterial occlusive disease. A careful physical examination, buttressed by monofilament testing for neuropathy and noninvasive testing for arterial insufficiency, can identify patients at risk for foot ulcers and appropriately classify patients who already have ulcers or other diabetic foot complications. Patient education regarding foot hygiene, nail care and proper footwear is crucial to reducing the risk of an injury that can lead to ulcer formation. Adherence to a systematic regimen of diagnosis and classification can improve communication between family physicians and diabetes subspecialists and facilitate appropriate treatment of complications. This team approach may ultimately lead to a reduction in lower extremity amputations related to diabetes. (American Family Physician 1998;57(6):1325-1332)

Discussion:

Peripheral arterial occlusive disease is four times more prevalent in diabetics than in nondiabetics.The arterial occlusion typically involves the tibial and peroneal arteries but spares the dorsalis pedis artery. Smoking, hypertension and hyperlipidemia commonly contribute to the increased prevalence of peripheral arterial occlusive disease in diabetics.

The presence of lower extremity ischemia is suggested by a combination of clinical signs and symptoms plus abnormal results on noninvasive vascular tests. Signs and symptoms may include claudication, pain occurring in the arch or forefoot at rest or during the night, absent popliteal or posterior tibial pulses, thinned or shiny skin, absence of hair on the lower leg and foot, thickened nails, redness of the affected area when the legs are dependent, and pallor when the foot is elevated.

Noninvasive vascular tests include transcutaneous oxygen measurement, the ankle-brachial index (ABI) and the absolute toe systolic pressure. The ABI is a noninvasive test that can be performed easily in the office using a handheld Doppler device. A blood pressure cuff is placed on the upper arm and inflated until no brachial pulse is detected by the Doppler device. The cuff is then slowly deflated until a Doppler-detected pulse returns (the systolic pressure). This maneuver is repeated on the leg, with the cuff wrapped around the distal calf and the Doppler device placed over the dorsalis pedis or posterior tibial artery. The ankle systolic pressure divided by the brachial systolic pressure gives the ABI.
 

Conclusions:

A variety of wound classification systems exists. This review outlines one diabetic foot classification system that is presently being evaluated to determine if its use will reduce the incidence of diabetic foot amputations. This classification system divides the findings for the diabetic foot into six categories based on increasing risk. The first three categories are risk factors for foot ulceration, and the second three are risk factors for amputation. The suggested treatments reflect the degree of risk for each category.

Recognition of risk factors, preventive foot maintenance and regular foot examinations are essential in preventing foot ulcers in patients with diabetes. When foot ulcers develop despite preventive measures, a systematically applied regimen of diagnosis and classification, coupled with early and appropriate treatment, should help to reduce the tremendous personal and societal burden of diabetes-related amputations.

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