Peter Blombery

Infusion of Reconstituted High-Density Lipoprotein Leads to Acute Changes in Human Atherosclerotic Plaque

Studies have shown a reduction in plaque volume and change in plaque ultrasound characteristics after 4 infusions of reconstituted high-density lipoprotein (rHDL). Whether rHDL infusion leads to acute changes in plaque characteristics in humans is not known. Patients with claudication scheduled for percutaneous superficial femoral artery revascularization were randomized to receive 1 intravenous infusion of either placebo or rHDL (80 mg/kg given over 4 hours). Five to 7 days following the infusion, patients returned and revascularization was performed including atherectomy to excise plaque from the superficial femoral artery. Twenty patients (17 males) average age, 68±10 years (mean±SD) were recruited. Eleven patients had a history of documented coronary artery disease, all patients were on aspirin, and 18 were on statins. Ten of the patients received rHDL and 10 placebo. There was significantly less vascular cell adhesion molecule-1 expression (28±3% versus 50±3%; P<0.05) and a reduction in lipid content in the plaque of HDL-treated subjects compared to placebo. The level of HDL cholesterol increased by 20% after infusion of rHDL and the capacity of apolipoprotein B–depleted plasma to support cholesterol efflux increased. Intravenous infusion of a single dose of reconstituted HDL led to acute changes in plaque characteristics with a reduction in lipid content, macrophage size, and measures of inflammation. These changes may contribute to the cardioprotective effects of HDL.

Hydrocortisone-induced hypertension in humans: pressor responsiveness and sympathetic function.

Oral hydrocortisone increases blood pressure and enhances pressor responsiveness in normal human subjects. We studied the effects of 1 week of oral hydrocortisone (200 mg/day) on blood pressure, cardiac output, total peripheral resistance, forearm vascular resistance, and norepinephrine spillover to plasma in eight healthy male volunteers. Although diastolic blood pressure remained unchanged, systolic blood pressure increased from 119 to 135 mm Hg (SED±3.4, p < 0.0l), associated with an increased cardiac output (5.85–7.73 l/min, SED±0.46, p < 0.01). Total peripheral vascular resistance fell from 15.1 to 12.2 mm Hg/l/min (SED±1.03, p < 0.05). Restmg forearm vascular resistance remained unchanged, but the reflex response to the cold pressor test was accentuated, the rise in resistance increasing from 10.5 mm Hg/ml/100 ml/min (R units) before treatment to 32.6 R units after treatment (SED±6.4, p < 0.025). The rise in forearm vascular resistance accompanying intra-arterial norepinephrine (25, 50, and 100 ng/ min) was also significantly greater after hydrocortisone, increasing from an average of 14.9±2.4 R units before treatment to 35.1±5.5 R units after hydrocortisone (SED±6.0, p < 0.05). A shift to the left in the dose-response relation and fall in threshold suggested increased sensitivity to norepinephrine after treatment. Measurement of resting norepinephrine spillover rate to plasma and norepinephrine uptake indicated that overall resting sympathetic nervous system activity was not increased. The rise in resting blood pressure with hydrocortisone is associated with an increased cardiac output (presumably due to increased blood volume). The increased responsiveness of the peripheral vasculature to reflex pressor stimuli appears to be due to changes in end-organ responsiveness since similar changes occurred with local administration of norepinephrine.

Ramipril Reduces Large-Artery Stiffness in Peripheral Arterial Disease and Promotes Elastogenic Remodeling in Cell Culture

Ramipril improves cardiovascular outcome in patients with peripheral arterial disease; however, the precise mechanisms of benefit remain to be elucidated. The effect of ramipril on large-artery stiffness in patients with peripheral arterial disease was examined. In addition, we determined the effect of ramiprilat on extracellular matrix from human aortic smooth muscle cell culture. Forty patients with peripheral arterial disease were randomized to receive ramipril, 10 mg once daily or placebo for 24 weeks. Arterial stiffness was assessed globally via systemic arterial compliance and augmentation index (carotid tonometry and Doppler velocimetry), and regionally via carotid–femoral pulse wave velocity. Angiotensin-converting enzyme inhibition increased arterial compliance by 0.10±0.02 mL/mm Hg, (P<0.001, all probability values relative to placebo) and reduced pulse wave velocity by 1.7±0.2 m/s (P<0.001), augmentation index by 4.1±0.3% (P<0.001), and systolic blood pressure by 5±1 mm Hg (P<0.001). Ramipril did not reduce mean arterial pressure significantly compared with placebo (P=0.59). In cell culture, ramiprilat decreased collagen deposition by >50% and increased elastin and fibrillin-1 deposition by >3- and 4-fold respectively (histochemistry and immunohistochemistry). Fibrillin-1 gene expression was increased 5-fold (real-time reverse-transcriptase polymerase chain reaction). Ramiprilat also reduced gene and protein (Western) expression of both matrix metalloproteinase (MMP)-2 and MMP-3. In conclusion, ramipril promoted an elastogenic matrix profile that may contribute to the observed clinical reduction in large-artery stiffness and carotid pressure augmentation, which occurred independently of mean arterial blood pressure reduction in patients with peripheral arterial disease.

Effect of Ramipril on Walking Times and Quality of Life Among Patients With Peripheral Artery Disease and Intermittent Claudication: A Randomized Controlled Trial

IMPORTANCE Approximately one-third of patients with peripheral artery disease experience intermittent claudication, with consequent loss of quality of life. OBJECTIVE To determine the efficacy of ramipril for improving walking ability, patient-perceived walking performance, and quality of life in patients with claudication. DESIGN, SETTING, AND PATIENTS Randomized, double-blind, placebo-controlled trial conducted among 212 patients with peripheral artery disease (mean age, 65.5 [SD, 6.2] years), initiated in May 2008 and completed in August 2011 and conducted at 3 hospitals in Australia. INTERVENTION Patients were randomized to receive 10 mg/d of ramipril (n = 106) or matching placebo (n = 106) for 24 weeks. MAIN OUTCOME MEASURES Maximum and pain-free walking times were recorded during a standard treadmill test. The Walking Impairment Questionnaire (WIQ) and Short-Form 36 Health Survey (SF-36) were used to assess walking ability and quality of life, respectively. RESULTS At 6 months, relative to placebo, ramipril was associated with a 75-second (95% CI, 60-89 seconds) increase in mean pain-free walking time (P < .001) and a 255-second (95% CI, 215-295 seconds) increase in maximum walking time (P < .001). Relative to placebo, ramipril improved the WIQ median distance score by 13.8 (Hodges-Lehmann 95% CI, 12.2-15.5), speed score by 13.3 (95% CI, 11.9-15.2), and stair climbing score by 25.2 (95% CI, 25.1-29.4) (P < .001 for all). The overall SF-36 median Physical Component Summary score improved by 8.2 (Hodges-Lehmann 95% CI, 3.6-11.4; P = .02) in the ramipril group relative to placebo. Ramipril did not affect the overall SF-36 median Mental Component Summary score. CONCLUSIONS AND RELEVANCE Among patients with intermittent claudication, 24-week treatment with ramipril resulted in significant increases in pain-free and maximum treadmill walking times compared with placebo. This was associated with a significant increase in the physical functioning component of the SF-36 score. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00681226.

Brief Communication: Ramipril Markedly Improves Walking Ability in Patients with Peripheral Arterial Disease: A Randomized Trial

Context Few therapies substantially reduce symptoms and improve exercise performance in patients with peripheral arterial disease (PAD). Contribution In this double-blind trial, investigators randomly assigned 40 older adults without diabetes and with symptomatic PAD to receive either ramipril or placebo, 10 mg once daily for 24 weeks. Compared with placebo, ramipril increased maximum and pain-free walking time and walking speed and distance. Cautions The trial was small and involved selected patients with limited mobility and exercise tolerance. Implications Ramipril may improve symptoms in some patients with PAD. The Editors This article has been retracted. See Notice of Retraction. Peripheral arterial disease (PAD) is a common disorder, with 12% of adults older than 50 years of age having an anklebrachial index (ABI) that is diagnostic of PAD (<0.9) (1). Approximately one third of these patients experience intermittent claudication during walking, limiting normal activities. Medical treatments to improve walking distance are limited. The angiotensin-converting enzyme (ACE) inhibitor ramipril reduced cardiovascular morbidity and mortality compared with placebo in patients with established atherosclerotic disease, including PAD, in the Heart Outcomes Prevention Evaluation (HOPE) study (2). This effect seemed to be independent of blood pressure reduction (3) and may relate to the known benefits of ACE inhibitors on both coronary and brachial endothelial function (4). No previous controlled studies have investigated the effect of ACE inhibitors on symptoms of intermittent claudication. Given the positive effects of ramipril in the HOPE trial and its convenient once-daily dosing formulation, we hypothesized that therapy with ramipril would improve intermittent claudication symptoms. We aimed to examine the effect of 6-month ramipril therapy on walking distance and claudication pain in a defined group of patients with claudication due to infrainguinal PAD by using a double-blind, randomized, placebo-controlled design. Methods This article has been retracted. See Notice of Retraction. We screened 152 patients with PAD from general practice clinics in the Melbourne, Australia, metropolitan area (Figure 1). Of them, 40 patients (mean age, 66 years [SD, 4]) were recruited and completed the trial. All patients gave written informed consent to participate in the study. The Ethics Committee of the Alfred Hospital, Melbourne, Australia, approved the study, and we performed the study in accordance with the Declaration of Helsinki 2000. All participants had an ABI less than 0.9 at rest in at least 1 leg; had a history of intermittent claudication (unilateral or bilateral), which was stable for 6 months; had evidence of superficial femoral artery stenosis or occlusion on duplex ultrasonography; had blood pressure of 160/90 mm Hg or less; had a stable medication regimen for at least 6 months; and had not previously been treated with ACE inhibitors. We excluded patients with limiting coronary artery disease, renal failure, history of hypertension, or type 2 diabetes mellitus. Figure 1. Flow of patients through the study. Computer-generated numbers specified the allocation sequence. A tamper-proof randomization process generated by the hospital research center randomly assigned participants into blocks of 10 to receive either ramipril (Tritace, Aventis Pharma Pty. Ltd., Macquarie Park, Australia, 10 mg once daily for 24 weeks) or placebo (10 mg once daily for 24 weeks) in a parallel-group, double-blind design. Both investigators and patients were blinded to drug assignment. Furthermore, investigators did not have access to baseline data when they performed follow-up measurements and patients were not asked which treatment they thought they were receiving. No patient assigned to placebo crossed over to ramipril during the trial or vice versa. We advised participants to maintain all aspects of their lifestyle throughout the trial and requested them to refrain from exercise, smoking, and caffeine for 24 hours before all testing. On the morning of testing, patients rested in a supine position for 15 minutes in a quiet room before the measurements. We assessed blood pressure, ABI, walking distance, duplex ultrasounds of leg arteries, and the Walking Impairment Questionnaire (WIQ) scores before and after both interventions. We advised patients about potential side effects and requested that they report any adverse event to the study coordinator. All patients performed a treadmill exercise test at a speed of 3.2 km/h and a grade of 12% (5), and we recorded pain-free walking time (time to onset of claudication pain) and maximum walking time. In our study, all patients reached a maximal level of claudication pain that limited exercise during the graded treadmill test. The WIQ was developed and validated against treadmill walking and is used to evaluate limitations in community-based walking ability (6). The WIQ assessed walking distance, speed, and stair-climbing ability, using a weighted standardized formula and returning a summary score between 0% and 100% (6, 7). Statistical Analyses All analysts were blinded to treatment assignment, and an independent investigator double-checked all measurement calculations and database entries. The study was powered to detect a 180-second change in maximum walking time with ramipril, assuming a standard deviation of 250 seconds ( = 0.05 [2-sided]; power, 86%). We compared 24-week changes from baseline in pain-free walking time, maximum walking time, and WIQ scores between treatments by using an analysis of covariance model with terms for treatment and baseline value as the analysis end points. We log-transformed the WIQ data to achieve a normal distribution before analysis. We conducted all statistical analyses by using Stata software, version 8.2 (Stata Corp., College Station, Texas). We expressed normally distributed data as means (SDs) or 95% CIs and non-normally distributed data as medians (ranges). A P value less 0.05 was deemed to be significant. No data were missing for any clinical variable measured in our study. Role of the Funding Sources This work was funded by the National Health and Medical Research Council of Australia. Aventis Pharma Pty. Ltd. provided ramipril (Tritace) and matching placebo capsules but provided no other funding for the study or to the investigators. The funding sources had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication. Results This article has been retracted. See Notice of Retraction. The ramipril and placebo groups were similar in age, other cardiovascular risk factors, medication use, and PAD severity, as evidenced by clinical symptoms (walking times), WIQ scores, and resting ABI (Table). No patient was taking cilostazol or pentoxifylline. On duplex ultrasonography, 6 of 40 patients had a superficial femoral artery occlusion (2 placebo patients and 4 ramipril patients), and the remaining patients had stenotic disease in the superficial femoral artery. Only 25% of patients were taking antiplatelet or lipid-lowering therapy. No adverse events were reported. Table. Baseline Characteristics AnkleBrachial Index Ramipril significantly increased ABI both at rest (change with placebo, 0.05 mm Hg [SD, 0.04]; change with ramipril, 0.07 mm Hg [SD, 0.08]; P< 0.001) and after exercise (change with placebo, 0.04 mm Hg [SD, 0.05]; change with ramipril, 0.08 mm Hg [SD, 0.14]; P< 0.001). At rest, this increase was due to reduction in brachial systolic blood pressure with ramipril treatment (0.85 mm Hg [SD, 1.57] vs. 5.05 mm Hg [SD, 2.33]; P< 0.001) rather than an increase in limiting leg pressure (0.75 mm Hg [SD, 1.71] vs. 0.15 mm Hg [SD, 1.27]; P= 0.26). After exercise, both a reduction in brachial pressure (change with placebo, 0.30 mm Hg [SD, 2.45]; change with ramipril, 6.80 mm Hg [SD, 6.07]; P< 0.001) and an increase in limiting leg pressure (change with placebo, 5.40 mm Hg [SD, 7.56]; change with ramipril, 7.10 mm Hg [SD, 4.59]; P< 0.001) contributed to the increase in ABI. Treadmill Test After adjustment for the baseline pain-free walking time, mean pain-free walking time after ramipril treatment was 227 seconds (95% CI, 175 seconds to 278 seconds; P< 0.001) longer than after placebo treatment (Figure 2). Similarly, maximum walking time significantly improved over the 24-week treatment period by 451 seconds (CI, 367 seconds to 536 seconds; P< 0.001) in the ramipril group after adjustment for baseline values (Figure 2). The lack of change observed over the 24-week treatment period in the placebo group (change in mean walking time, 10 seconds [SD, 9] [CI, 14 seconds to 6 seconds]; P< 0.001) may reflect both the advanced age of participants and the fact that they all had limiting infrainguinal disease, which would probably give more reproducible treadmill data than aortoiliac disease. In addition, we asked patients to maintain all aspects of their lifestyle throughout the trial. Figure 2. Effect of ramipril on maximum treadmill walking times. Walking Impairment Questionnaire Ramipril improved WIQ median distance score from 5% (range, 1% to 39%) to 21% (range, 12% to 58%) (P< 0.001), speed score from 3% (range, 3% to 39%) to 18% (range, 8% to 50%) (P< 0.001), and stair-climbing score from 17% (range, 4% to 80%) to 67% (range, 38% to 88%) (P< 0.001). Duplex Ultrasonography Volume flow was unaltered in the limiting leg at the stenotic site. However, ramipril significantly increased volume flow in the common femoral artery proximal to the site of stenosis in both the limiting leg (change with placebo, 0.014 L/min [SD, 0.022]; change with ramipril, 0.017 L/min [SD, 0.034]; P= 0.008) and the nonlimiting leg (change with placebo, 0.006 L/min [SD, 0.041]; change with ramipril, 0.019 L/min [SD, 0.019]; P= 0.035). Discussion This article has been retracted. See Notice of Retraction. Our study shows that treatment

Reduced arterial stiffness may contribute to angiotensin-converting enzyme inhibitor induced improvements in walking time in peripheral arterial disease patients.

Objective Claudication is a debilitating consequence of peripheral arterial disease. Evidence is accumulating to suggest that large artery stiffness may influence peripheral perfusion and walking time through effects on peripheral hemodynamics as well as microvascular structure and function. We have previously shown that the angiotensin-converting enzyme inhibitor ramipril increased systemic arterial compliance by 64%, and increased maximum walking time by over 200% in patients with peripheral arterial disease. In the current analysis in the same patient cohort, we hypothesized that this relationship may, in part, be causal. Methods Forty patients with peripheral arterial disease [66 ± 4 years (mean ± SD); n = 20 per group] were randomized to ramipril, 10 mg once daily, or placebo for 24 weeks in a double-blind study. Maximum walking time was recorded during a standard treadmill test. Indices of arterial stiffness were assessed globally by systemic arterial compliance and augmentation index and regionally via central pulse wave velocity. Results Ramipril increased maximum walking time by 243% and improved arterial stiffness parameters by between 17 and 64% (all P < 0.001 compared with placebo). There were moderately strong correlations between the pre/post intervention change in maximum walking time and the change in indices of arterial stiffness (systemic arterial compliance, r = 0.65, P < 0.001; central pulse wave velocity, r = −0.57, P < 0.001; augmentation index, r = −0.79, P < 0.001; time to pressure augmentation, r = 0.52, P = 0.001). Conclusion The present data support the hypothesis that the beneficial effects of ramipril on maximum walking time observed in our peripheral arterial disease population are, at least partly, a consequence of reduced arterial stiffness.

Venous thromboembolism prophylaxis guideline implementation is improved by nurse directed feedback and audit

BackgroundVenous thromboembolism (VTE) is a major health and financial burden. VTE impacts health outcomes in surgical and non-surgical patients. VTE prophylaxis is underutilized, particularly amongst high risk medical patients. We conducted a multicentre clinical audit to determine the extent to which appropriate VTE prophylaxis in acutely ill hospitalized medical patients could be improved via implementation of a multifaceted nurse facilitated educational program.MethodsThis multicentre clinical audit of 15 Australian hospitals was conducted in 2007-208. The program incorporated a baseline audit to determine the proportion of patients receiving appropriate VTE prophylaxis according to best practice recommendations issued by the Australian and New Zealand Working Party on the Management and Prevention of Venous Thromboembolism (ANZ-WP recommendations), followed by a 4-month education intervention program and a post intervention audit. The primary endpoint was to compare the proportion of patients being appropriately managed based on their risk profile between the two audits.ResultsA total of 8774 patients (audit 1; 4399 and audit 2; 4375) were included in the study, most (82.2% audit 1; and 81.0% audit 2) were high risk based on ANZ-WP recommendations. At baseline 37.9% of high risk patients were receiving appropriate thromboprophylaxis. This increased to 54.1% in the post intervention audit (absolute improvement 16%; 95% confidence interval [CI] 11.7%, 20.5%). As a result of the nurse educator program, the likelihood of high risk patients being treated according to ANZ-WP recommendations increased significantly (OR 1.96; 1.62, 2.37).ConclusionUtilization of VTE prophylaxis amongst hospitalized medical patients can be significantly improved by implementation of a multifaceted educational program coordinated by a dedicated nurse practitioner.

Notice of Retraction: Ahimastos AA, et al. Effect of Ramipril on Walking Times and Quality of Life Among Patients With Peripheral Artery Disease and Intermittent Claudication: A Randomized Controlled Trial. JAMA. 2013;309(5):453-460.

In Reply We agree with Drs Redington and Caldarone that many animal and human studies have shown that a single or few (≤5) short episodes of remote ischemic preconditioning (typically 5 minutes of limb ischemia followed by 5 minutes of reperfusion) are protective for many organs (including the heart, brain, and kidney) with few reported adverse effects. However, few studies have examined the long-term effects of repeated episodes of remote ischemic preconditioning, and this is what we referred to in our Editorial that the effects of multiple episodes of remote ischemic preconditioning, which patients may be exposed to if remote ischemic preconditioning is widely used, are unclear. For example, the study by Meng et al1 used remote ischemic preconditioning twice daily during 300 consecutive days to reduce stroke, but did not examine molecular mechanisms of brain protection or cardiovascular adverse effects. Similarly, a study by Shaked et al2 that used intermittent cycles of remote ischemic preconditioning as adjunctive therapy for treatment of diabetic foot ulcers did not examine cardiovascular effects. Redington appeared to agree with our point of view as the coauthor of a review article,3 which cautioned that “hyperconditioning (ie, an as-yet undefined, excessive number of conditioning episodes) may be deleterious.” Another recent review article by Whittaker and Przyklenk4 suggested that in addition to tachyphylaxis (ie, increased tolerance to the effect of an intervention), repeated episodes of limb ischemia may have unfavorable consequences for collagen and systemic effects mediated via matrix metalloproteinases. The authors concluded that the benefits of protection against ischemia may be found at low doses (ie, low number and duration of preconditioning episodes), but these benefits may be lost and adverse effects may occur (collagen damage) at high doses. In addition, remote ischemic preconditioning may have limited utility for cardioprotection in 2 large populations (elderly patients and those with diabetes) at high risk for cardiovascular diseases,5 and may be associated with higher risk for atrial fibrillation, even when used at the conventional dose (5-minute episodes of ischemia/reperfusion repeated 5 times) before coronary artery bypass graft surgery.6 Therefore, even though we share the enthusiasm of Redington and Caldarone for the promise of remote ischemic preconditioning for organ protection, investigators in the field should examine potential long-term harmful effects to various organs, including the heart, particularly when hyperconditioning is used.

Notice of retraction: Ramipril markedly improves walking ability in patients with peripheral arterial disease

TO THE EDITOR: Following admission of data fabrication by the first author, Anna Ahimastos, in a similar study of ramipril for patients with peripheral arterial disease (1), Baker IDI Heart and Diabetes Institute conducted an independent investigation of the trial, published in Annals in 2006 (2). Based on that investigation and our own analysis, we, the undersigned authors, wish to retract this article due to an inability to adequately validate primary data sources. Dr. Ahimastos maintains the integrity of the data and validity of reported results and has declined to answer additional questions. The investigation did not find culpability on our part, and we apologize unreservedly to the editors, reviewers, and readers of Annals of Internal Medicine. Given the clinical indications for ramipril and other angiotensin-converting enzyme inhibitors, we believe there is no risk that these possibly invalid trial data harmed trial participants or patients with peripheral arterial disease taking ramipril. Editors Note: The above-named authors agreed to this retraction. Attempts on the part of the journal office to obtain input regarding this retraction from Dr. Ahimastos, first author of the retracted article, were unsuccessful.

387 EFFECT OF RAMIPRIL THERAPY ON WALKING ABILITY AND QUALITY OF LIFE IN PATIENTS WITH INTERMITTENT CLAUDICATION

Background: One third of patients with peripheral artery disease (PAD) experience intermittent claudication, with the major consequence being loss of quality of life. This study was conducted to determine the efficacy of ramipril in improving walking ability and quality of life in patients with PAD. Design and Methods: 200 PAD patients (66 ± 6 years (mean ± SD) were randomised to receive ramipril, 10 mg once daily (n = 99) or placebo (n = 101) for 24 weeks in a double blind study. Pain free walking time (PFWT) and maximum walking time (MWT) were determined using a standard exercise treadmill test. The standard Walking Impairment Questionnaire (WIQ) and Short Form-36 (SF-36) questionnaire were administered to quantify walking ability and quality of life respectively. Results: Ramipril increased PFWT by 92% (Placebo 8.9 ± 2 secs; Ramipril 87.2 ± 65.8; p < 0.0001) and MWT by 139% (Placebo 14.4 ± 32.9 secs; Ramipril 192.7 ± 125.9; p < 0.0001). The treatment group reported significantly higher scores on the distance (Placebo −3.4 ± 7.0; Ramipril 12.4 ± 9.5; p < 0.0001), speed (Placebo −3.2 ± 4.5; Ramipril 11.1 ± 7.8; p < 0.0001) and stair climbing (Placebo −7.1 ± 10.5; Ramipril 23.8 ± 18.7; p < 0.0001) subscales of the WIQ. The treatment group also reported higher scores on the physical functioning subscale of the SF-36 (Placebo −0.1 ± 0.9, Ramipril 2.1 ± 2.8; p < 0.0001). Conclusions: This is thefirst adequately powered randomized trial demonstrating that ACE inhibition improves walking ability and quality of life in patients with PAD; an improvement substantially beyond that reported with conventional medical therapies.