Vascular Medicine

Treadmill testing is used to estimate the severity of claudication, but routine use is not practical or cost-effective in all settings. Thus, the purposes of this study were: (1) to develop and cross-validate prediction equations for treadmill claudication pain distances in a heterogeneous cohort of peripheral arterial occlusive disease patients, and (2) to determine if the regression equations were more accurate in assessing claudication distances than self-reported distances of patients. Medical history, vital signs, resting ankle/brachial systolic pressure index (ABI), and claudication distances during a graded treadmill test were obtained on a validation group of 178 claudicants and on a cross-validation group of 94 claudicants. The independent predictors of claudication pain distances of the validation group were ABI, body mass index, gender, and current smoking status, with multiple correlation coefficients of R=0.73 and R=0.82 for the distances to onset and to maximal pain, respectively. These equations were successfully cross-validated on an independent group of claudicants, as the predicted distances to onset of claudication pain (167.2± 102.6 m) and to maximal pain (354.6± 154.3 m) were similar (p=0.99) to measured distances (169.1 ± 127.8 m and 356.6±181.0 m, respectively). However, the self-reported distances to onset (89.5± 126.3) and to maximal claudication pain (189.2±284.3) were 1–2 blocks less than either the measured or predicted distances (p<0.01). It is concluded that claudication pain distances during an incremental treadmill test can be more accurately estimated from a composite of variables obtained during medical screening than by relying on the self-report of patients. Consequently, in clinical settings where treadmill testing is impractical, the functional severity of claudication can be assessed without exercise testing.

To determine whether heparin administered by continuous intravenous infusion using a nomogram is superior to a random dosing scheme, we performed a prospective, randomized comparative trial in 161 patients. Patients were prospectively randomized to one of three groups. Group I received an intravenous bolus of 5000 IU of heparin followed by heparin administration according to a modification of a previously published nomogram. Group II patients received a 5000 IU intravenous bolus of heparin followed by continuous intravenous heparin infusion with dosage adjustment at the discretion of the treating physician. Group III patients received a continuous intravenous heparin infusion with dosage adjustments at the discretion of the treating physician without the prior administration of a bolus dose. Activated partial thromboplastin time (APTT) was obtained at baseline, 6 h after each heparin dose adjustment and every morning. The mean percent of each patient's APTTs in the subtherapeutic range (<50 sec) over the course of treatment was 9% for group I and 24% for groups II and III, p=0.0001. The three groups had a similar percentage of each patient's APTTs within the therapeutic range (50–80 sec). There was a larger percentage of APTTs >80 sec in group I (46%) compared to group II (31%) or group III (32%), p=0.01. There were no clinically recurrent deep venous thrombi or arterial thromboemboli in any of the groups. Two patients had documented pulmonary emboli during heparin therapy (one in group I; one in group II). There was no difference in the complication rates of heparin therapy or the need for blood transfusions among the three groups. Patients randomized to the heparin nomogram (group I) achieved an APTT >50 sec more frequently than patients in the other two groups. Overall, fewer patients in the nomogram group were subtherapeutic, and, when APTT levels fell in the subtherapeutic range, the nomogram restored APTTs to the therapeutic range faster than the standard methods. The heparin nomogram was clearly more effective as a method of heparin dosing than standard methods of anticoagulation dosing.

Hypothermia has pathophysiological consequences on endothelial and smooth muscle cell function. This study investigates the impact on venous relaxation of hypothermia and rewarming following hypothermic exposure. In vitro isometric relaxation responses of norepinephrine precontracted rabbit external jugular veins to a panel of endothelium-dependent and -independent agonists were assessed in controls at 37°C, and in an experimental group after cooling to 20°C and after rewarming to 37°C. On cooling, the endothelium-dependent responses to acetylcholine became multiphasic with initial contraction at low concentrations followed by relaxation at higher concentrations, the maximum of which was significantly diminished compared to controls. Incubation with indomethacin did not affect this response. Rewarming re-established a monophasic dose-dependent acetylcholine induced relaxation response but the maximal response was significantly augmented. This augmentation in relaxation on rewarming could be prevented by preincubation with indomethacin. The maximal response to calcium ionophore was reduced at 20°C and augmented upon rewarming to 37°C. All veins relaxed in a dose-dependent manner to the nonendothelium-dependent agonists forskolin and sodium nitroprusside; the maximal responses were significantly reduced at 20°C and returned to normal upon rewarming. This study suggests that short-term exposure of venous tissue to hypothermia impairs the vessel's ability to produce endothelium-dependent relaxation. Rewarming does not re-establish normal endothelium-dependent relaxation but results in an enhanced, partially indomethacin-sensitive, response which appears to be independent of changes in nonendothelium-dependent mediated relaxation.

There is recent interest in the possibility that angiotensin converting enzyme inhibitors (ACE inhibitors) may reduce the damage inflicted on the arterial wall by common cardiovascular risk factors such as hypertension, hyperlipidaemia and ageing. The efficacy of these drugs in blood pressure reduction is accepted, but whether there is an excess benefit on arterial structure and function, conferred by use of ACE inhibitors over more traditional antihypertensives, is still under debate. There is also evidence in animal models to suggest that ACE inhibition is effective in reduction of arterial damage due to experimental hyperlipidaemia.

ACE inhibitors not only reduce the conversion of angiotensin I and angiotensin II, which can interact with the sympathetic nervous system, but also prevent the degradation of bradykinin. This means that ACE inhibitors have several potential mechanisms through which they could suppress intimai hypertrophy and prevent endothelial dysfunction, which is believed to precede arteriosclerosis in man.

Although much further work is needed to clarify the mechanism underlying the beneficial effects on the arterial wall of this group of drugs, they do appear to have significant potential in the effort to reduce cardiovascular mortality and morbidity, especially in high risk groups.

Although duplex ultrasonography offers a number of theoretical and practical advantages over arteriography for the assessment of lower limb arterial disease, it has not yet been widely accepted into clinical practice. This article reviews the current status of lower limb arterial duplex and concludes that arteriography should no longer be regarded as the diagnostic ‘gold-standard’ and that duplex ultrasonography should now be the first line investigation in patients with lower limb arterial disease.

Aspirin and carotid endarterectomy represent the current method of prophylaxis against stroke in patients with symptomatic high grade carotid stenoses. Whilst balloon dilatation and stent placement is an accepted form of recannalization, elsewhere in the arterial circulation the technique is in its infancy within the supra-aortic vessels. Carotid endarterectomy is expensive, requires a general anaesthetic and is associated with an acceptable complication rate as demonstrated by the ECST and NASCET studies. The author's experience in 55 patients with symptomatic high grade atherosclerotic disease is described with a disabling stroke rate at 30 days similar to the surgical series (5%). Long-term follow-up is awaited. Metallic intra-arterial stents provide the opportunity to reduce the immediate postintervention residual stenosis and possibly reduce the long-term restenosis rate. Modifications of the technique are in development and may reduce the cerebral embolization that occurs during the procedure.

Although some form of quality control assessment is standard practice following virtually all forms of peripheral vascular reconstruction, it is seldom applied to carotid endarterectomy. This is despite the fact that the complications following endarterectomy can be catastrophic, are often related to technical error and are not easily remedied. A number of novel quality control techniques are now available. This review article summarizes the application of these methods to ensuring optimal surgical practice in patients undergoing carotid endarterectomy.

A total of 3899 patients over 40 years old who had documented intermittent claudication for at least 2 months and in whom the ratio of systolic blood pressure in the ankle to that in the arm was <0.85 in both arteries of at least one foot were recruited in a double-blind, randomized, placebo-controlled trial after a single-blind run-in period of placebo treatment for 1 month. Trial drug was ketanserin 40 mg three times daily.

The first primary event after randomization was the endpoint. Primary events were definite myocardial infarction, major stroke, amputation above the ankle, excision of ischaemic viscera, and death due to other vascular causes.

There were 136 study endpoints in the 1930 patients treated with ketanserin, who were followed up for 2063 patient-years, and 132 study endpoints in the 1969 patients treated with placebo, who were followed up for 2129 patient-years. A harmful interaction of ketanserin and potassium-losing diuretics resulted in an increase in the number of deaths. After patients taking potassium-losing diuretics or antiarrhythmic agents were excluded, a secondary analysis showed that there were 65 endpoints in 1514 patients taking ketanserin and 87 in 1577 patients taking placebo, a reduction of 23% in the number of study endpoints in those taking ketanserin.

The treadmill walking distance and ankle systolic pressure were measured in a predetermined subset of 594 patients. Complete datasets at the beginning and end of 1 year's treatment with ketanserin or placebo were available in 436 patients. There was no difference between the groups in the improvement in pain-free treadmill walking distance. The placebo effect on treadmill walking distance increased continuously for at least 1 year at the rate of about 15% every 6 months. There was no significant change in either group in the ankle systolic pressure at the end of the treatment period, but, in the group given ketanserin, brachial systolic pressure was decreased and the ankle/arm systolic pressure ratio therefore increased.

The mortality in patients with intermittent claudication can be reduced by treatment with ticlopidine. This is the clinically most significant result from STIMS, the Swedish Ticlopidine Multicenter Study. During an average treatment period of 5.6 years, 153 of the 687 patients died, 26.1% in the placebo group and 18.5% in the ticlopidine group (RR0.7, p=0.015). The incidence of fatal vascular events in the two groups was 12% and 6%. In terms of lives saved per years of treatment, STIMS showed that by treating 200 claudicants for 5 years one can save 13 from a cardiovascular death, not merely dying from something else as treatment was associated with a reduced total mortality as well. The interpretation of the on-treatment analysis is that for those who tolerate the drug the combined vascular morbidity and mortality rate is lowered from 24% to 14%. The disadvantage is that many patients do not tolerate ticlopidine. In STIMS, 22% (2.5 times as many as in the control group) had to stop medication because of gastrointestinal side-effects. Although ticlopidine is associated with an increased risk of leukopenia, the risk in absolute numbers is small: according to STIMS, 4% during 5.6 years. All events were reversible. The 1.4% incidence of thrombocytopenia did not seem to be associated with ticlopidine treatment.

This paper critically reviews the methodology used in clinical trials in chronic occlusive arterial disease (COAD) stage II (intermittent claudication) patients. The reasons for choosing internationally accepted standard treadmill settings as well as its limitations are discussed. Emphasis is put on the discussion of valid trial endpoints such as hemodynamic surrogates and clinically oriented parameters. Reasons for a spontaneous and treatment-unrelated improvement in claudication distance are elucidated, and variables which may be used for the definition of patient subsamples showing a high frequency of a pronounced treatment response (treatment responder populations) are presented. The magnitude of claudication distance improvement that might be considered clinically relevant is discussed in the light of the European Union guidelines for clinical trials in COAD patients. Results achieved with pentoxifylline are presented in context with all variables mentioned above.

The most serious threat to a claudicant is not the possible future need for a major amputation, but rather that the medium-term mortality is two to three times that of the general age-matched population. In patients with more severe disease in the legs, approximately 45% will have had a major amputation or be dead within a year of developing rest pain, ulcers or gangrene. These are the challenges for pharmacotherapy in peripheral arterial occlusive disease. In the short and medium term, pharmacotherapy can only have a significant effect by modifying the microcirculatory response to the low perfusion pressure caused by the arterial disease. The microcirculatory changes in the leg in severe leg ischaemia are ill understood, but theoretically a number of pharmacological effects could be beneficial. In practice, the only type of drugs widely tested clinically in severe leg ischaemia are prostacyclin and its analogues. In the last 12 years the results of properly controlled randomized trials involving patients with chronic limb ischaemia have been carried out in approximately 2000 patients in Europe. The largest number were entered into trials using the prostacyclin analogue iloprost. Some of these trials have shown a significant benefit compared to placebo in terms of major amputation or death during the 6 months following a 2–4-week course of intravenous iloprost. The possible future indications for this type of therapy, as well as the use for prostaglandins in claudicants, is discussed.

Patients with peripheral arterial occlusion may be treated with one of three distinct treatment strategies: observation and/or anticoagulation alone, operative intervention, or catheter-directed thrombolytic therapy. The severity of symptoms is the most important clinical parameter with which to formulate clinical strategies. Patients with non-lifestyle limiting claudication may be best managed without arteriographic investigation, managing symptoms conservatively with exercise, cessation of smoking, and occasionally the oral pharmacologic agent pentoxifylline. Patients with threatened limbs in the form of rest pain or tissue loss carry a high risk of limb loss without intervention. These patients should undergo arteriography with consideration of endovascular intervention for focal lesions and bypass grafting for more diffuse disease. Patients with more acute symptoms may be best treated with catheter-directed thrombolytic therapy, addressing unmasked lesions responsible for the occlusion with an operative or endovascular approach. In all cases, the appropriate therapy must be tailored to the clinical presentation, the anatomic distribution of disease, and the experience of the clinical team.