Effect of ramipril on renal function in patients with intermittent claudication.

BACKGROUND: The Heart Outcomes Prevention Study (HOPE) demonstrated that ramipril resulted in a blood-pressure-independent 25% reduction in cardiovascular events in patients with peripheral arterial disease (PAD). Despite this, general practitioners and vascular surgeons remain reluctant to prescribe ACE inhibitors in this group of patients because of concerns about renal artery stenosis (RAS). We aimed to define the effect of ramipril on renal function in patients with intermittent claudication (IC). METHODS AND RESULTS: Of 132 unselected patients with IC entering the study 78 (59%) were excluded due to: current ACE inhibitor use (38%), renal impairment (serum creatinine above normal range) (15%), known severe RAS (1%) or unwillingness to participate (5%). The remaining 54 patients were titrated to 10 mg ramipril and renal function was monitored at 1, 5, and 12 weeks. Treatment was discontinued during titration in 5 patients due to symptoms (3) or lack of compliance (2). In the remainder, median [IQR] serum creatinine increased (94 [85.8-103.3] to 98 [88.0-106.5] micromol/L, p < or = 0.001) and median [IQR] GFR decreased (71.5 [64.6-82.3] to 68.7 [59.8-74.7] mL/min per 1.73 m2, p < or = 0.001) between baseline and 5 weeks. These changes were not considered clinically significant. By 12 weeks these values had returned almost to baseline (Cr 95.5 [88.0-103.25] micromol/L, GFR 71.8 [65.3-77.4] mL/min). No patient had a serum creatinine rise > 30%. CONCLUSION: Most of patients with IC and a normal serum creatinine can be safely commenced on ramipril provided they are screened, titrated and monitored as described above. Studies in patients with borderline renal impairment (serum creatinine up to 30% above baseline) are on-going.

Assessment of smoking status in patients with peripheral arterial disease.

OBJECTIVE: To assess the utility of a novel rapid urinary cotinine assay to detect and quantify the level of smoking in patients with peripheral arterial disease. METHODS: This was a cross-sectional study in a vascular surgical outpatient department of a large teaching hospital. Participants were 100 consecutive subjects presenting to a hospital outpatient clinic with a diagnosis of intermittent claudication confirmed by a positive Edinburgh claudication questionnaire and an ankle-brachial pressure index of less than 0.9. Main outcome measures were patient-offered smoking history, exhaled breath carbon monoxide levels, urinary cotinine levels as measured by a novel rapid assay, and laboratory-measured creatinine-adjusted urinary cotinine levels. Results Fifty-five subjects declared that they were current smokers, 40 declared that they were ex-smokers, and 5 declared that they were never-smokers. Of the 40 ex-smokers, 6 subjects (15%) had urinary cotinine levels greater than 500 ng/mL (regular smokers), and a further 2 (5%) had urinary cotinine levels between 100 and 500 ng/mL (light, irregular, or passive smokers). The rapid urinary cotinine assay had a sensitivity and specificity of 100% and 98%, respectively, in its ability to detect active smoking, and the degree of smoking correlated well with laboratory creatinine-corrected urinary cotinine levels (Spearman coefficient, 0.805; P < .001). By contrast, exhaled carbon monoxide had a sensitivity and specificity of 95% and 89%, respectively, and although it correlated well with urinary cotinine (Spearman coefficient, 0.782; P < .001), it was found on linear regression analysis to be unreliable in differentiating light smokers from nonsmokers. CONCLUSIONS: Patient-offered smoking history is unreliable because there is no correlation between the patient-reported number of cigarettes smoked per day and urinary cotinine levels. The novel rapid assay for urinary cotinine described here is superior to exhaled carbon monoxide measurement in detecting the level of smoking exposure among patients with intermittent claudication, and its results correlate well with laboratory-measured cotinine.

Dietary folate and vitamin B6 are independent predictors of peripheral arterial occlusive disease.

BACKGROUND: It has been suggested that hyperhomocysteinemia (HHcy) is an independent risk factor for peripheral arterial occlusive disease (PAOD). However, the relationship between dietary folate and vitamin B6, cofactors in the metabolism of homocysteine (Hcy), and PAOD is unclear. AIMS: To study the relationship between dietary folate and B6 and PAOD. METHODS: Case-control population based study of 392 men older than 50 years living in Huntingdon, United Kingdom. PAOD, defined as an ankle-brachial pressure index (ABPI) < 0.9, was present in 86 (22%) of subjects. Folate, vitamin B6, and vitamin B12 intakes were calculated by means of the EPIC (European Prospective Investigation into Cancer) food frequency questionnaire. RESULTS: Daily folate intake was significantly lower in case subjects (mean, 288; 95% confidence interval [CI], 266-309 microg) than in control subjects (324; 95% CI, 313-335 microg). Daily vitamin B6 intake was also lower in case subjects (2.05; 95% CI, 1.92-2.19 mg versus 2.26; 95% CI, 2.19-2.33 mg). Daily folate and vitamin B6 intakes were independent predictors of PAOD after adjusting for age, blood pressure, cholesterol levels, diabetes, and smoking status in a logistic regression model. This model suggests that increasing daily folate intake by 1 standard deviation decreased the risk of PAOD by 46%. A similar increase in daily vitamin B6 intake decreased the risk of PAOD by 29%. CONCLUSION: In men older than 50 years, dietary folate and B6 intakes are independent predictors of PAOD. Longitudinal studies are required to determine whether dietary modification can reduce the incidence of PAOD in the population.

The prevalence of hyperhomocysteinemia, methylene tetrahydrofolate reductase C677T mutation, and vitamin B12 and folate deficiency in patients with chronic venous insufficiency.

INTRODUCTION: Hyperhomocysteinemia (HHcy) is a risk factor for venous thromboembolism, which in turn is a major cause of chronic venous insufficiency. HHcy may be more common in patients with chronic venous insufficiency, but the cause is unknown. METHODS: One hundred hospital outpatients (52 women; median age, 66.5 years [interquartile range, 53-77 years] with venous disease C(2-6) underwent assessment of serum vitamin B(12) and folate concentration, plasma Hcy concentration, and C677T methylene tetrahydrofolate reductase (MTHR) homozygosity with polymerase chain reaction. HHcy was defined as greater than 15 micromol/L, the 95th centile of the normal range. RESULTS: CEAP classification was C(2) in 39 patients, C(3) in 10 patients, C(4) in 13 patients, C(5) in 15 patients, and C(6) in 23 patients, with median Hcy concentration 11.6, 11.5, 12.5, 15.1, and 18.1 micromol/L, respectively (Kruskall-Wallis test, P <.001). Overall prevalence of HHcy was 39% (P <.001, binomial test vs normal population), and was significantly related (Pearson chi(2) for trend, 13.616; P <.009) to clinical grade: C(2), 23%; C(3), 20%; C(4), 39%; C(5), 53%; C(6), 65%. In a linear regression model, C(6) disease was a strong independent predictor (R(2) = 20.1%) for Hcy. Overall, 5 of 49 patients (10%, NS compared with normal population [5%]) with C(2-3) disease and 10 of 51 patients (20%) (P <.001, binomial test) with C(4-6) disease were homozygous for the C677T MTHFR polymorphism. Hcy levels and prevalence of HHcy were negatively correlated with vitamin B(12) levels (r = -0.248, P =.021, and r = -0.225;, P =.037, respectively). There was no significant relationship with folate. HHcy was present in 3 patients (all with C(5-6) disease) with either vitamin B(12) or folate deficiency, and in 8 of 15 patients homozygous for MTHFR C677T. No patient had HHcy, vitamin deficiency, and C677T mutation. CONCLUSION: HHcy is common in patients with chronic venous insufficiency, especially those with ulceration. However, inasmuch as fewer than a third of patients with HHcy were C677T MTHFR homozygous or had vitamin B(12) or folate deficiency, other mechanisms must be responsible in the majority. Further work is required to determine the cause of HHcy in chronic venous insufficiency, whether HHcy is causally related to development and progression of the disease, and whether treatment would be beneficial.

Are antihypertensive drugs associated with abdominal aortic aneurysms?

OBJECTIVE: The aim of this study was to investigate the association between anti-hypertensive drugs, the risk of developing an abdominal aortic aneurysm (AAA), aortic wall stiffness, collagen turnover, and change in aortic diameter. STUDY DESIGN, SETTINGS AND METHODS: Data on present medication, smoking status, and medical history of participants in two population-based aneurysm screening programs in the United Kingdom were collected by use of questionnaire. Aortic elasticity was measured by M-mode ultrasound scanning. A serum radioimmunoassay of the amino-terminal propeptide of type III procollagen was used to assess collagen turnover in one of the patient series. RESULTS: Data from 438 cases with an AAA >29 mm and 5373 controls were analyzed. Calcium-channel blockers were independently associated with AAA. The odds ratio of having an AAA was 2.6 (95% confidence interval [CI], 1.5-4.2) after adjusting for all relevant confounders. Other antihypertensive drugs showed no increased risk. No significant differences in growth rates were found in cases exposed to any of the main antihypertensive drugs. An increased collagen turnover was found in subjects receiving angiotensin-converting enzyme (ACE) inhibitors: 4.26 mg/L (95% CI, 3.73-4.79) compared with 3.62 mg/L (95% CI, 3.49-3.76) for subjects not receiving ACE inhibitors. No differences in type III collagen turnover was found with use of any other antihypertensive drug. The mean aortic wall stiffness was greater for all subjects exposed to calcium-channel blockers, whether with AAA or not: 25.1 arbitrary units (95% CI, 20.0-30.2) vs 19.3 (95% CI, 18.1-20.4)(P =.002). By contrast, the mean stiffness for cases receiving ACE inhibitors was smaller than for those not receiving ACE inhibitors: 19.0 (95% CI, 13.9-24.0) vs 25.2 (95% CI, 23.0-27.4). CONCLUSIONS: Calcium-channel blockers were an independent risk factor for the presence of an AAA and were associated with an increased arterial aortic wall stiffness. ACE inhibitors were associated with decreased stiffness and greater collagen turnover. No significant effects on the growth rate of small aneurysms were detected.