Clinical outcome in patients with peripheral artery disease. Results from a prospective registry (FRENA)

doi:10.1016/j.ejim.2007.09.003

European Journal of Internal Medicine

Volume 19, Issue 3, May 2008, Pages 192-197

https://doi.org/10.1016/j.ejim.2007.09.003 Get rights and content

Abstract

Background

The risk of future cardiovascular events in patients with peripheral artery disease (PAD) is often underestimated.

Patients and methods

FRENA is an ongoing, observational registry of consecutive outpatients with symptomatic PAD, coronary artery disease (CAD) or cerebrovascular disease (CVD). We compared the incidence of major cardiovascular events (i.e., myocardial infarction, ischemic stroke, critical limb ischemia, or cardiovascular death) during a 12-month follow-up period in a series of consecutive outpatients with PAD, CAD or CVD.

Results

As of December 2006, 1265 patients had been enrolled in FRENA who completed the 12-month follow-up. Of these, 417 patients (33%) had PAD, 474 (37%) had CAD, 374 (30%) had CVD. Patients with PAD had an increased incidence of major cardiovascular events per 100 patient-years: 17 (95% CI: 13–22) vs. 7.9 (5.5–11) in those with CAD, or 8.9 (6.1–13) in those with CVD. Compared to patients with CAD or CVD those with PAD had a similar incidence of myocardial infarction or stroke, but a higher incidence of critical limb ischemia, limb amputation and death. This incidence increased with the severity of the symptoms: 8.7 (95% CI: 5.3–13) in patients in Fontaine stage IIa; 25 (95% CI: 16–38) in stage IIb; 26 (95% CI: 13–47) in stage III; 42 (95% CI: 24–67) in stage IV.

Conclusions

Our data confirm a higher incidence of major cardiovascular events for patients with PAD, as well as a correlation of these events with the severity of PAD.

Introduction

Even in the absence of a history of coronary artery disease (CAD), patients with peripheral artery disease (PAD) have a similar risk to die from a cardiovascular cause as patients with previous CAD.[1], [2], [3] Indeed, these patients are usually considered for secondary prevention strategies comparable to those for patients with CAD or cerebrovascular disease (CVD).[4], [5] However, despite its frequency and severity, data on cardiovascular morbidity and mortality of patients with symptomatic PAD are scarce.[6], [7], [8], [9], [10], [11]

The FRENA (Factores de Riesgo y ENfermedad Arterial) Registry is an ongoing, multicentre, observational registry of consecutive patients with symptomatic ischemic disease in the heart, brain, and/or major peripheral arteries. The aim of this study was to compare the incidence of major cardiovascular events during a 12-month follow-up period in patients with PAD, CAD or CVD.

Section snippets

Inclusion criteria

Participating hospitals in the FRENA registry prospectively enroll consecutive outpatients with cardiovascular disease meeting at least one recent (< 3 months prior to enrollment) episode of CAD (manifesting as angina or acute coronary syndrome); CVD (manifesting as transient ischemic attack or ischemic stroke); or PAD (either intermittent claudication with an ankle–brachial index < 0.9, or previous vascular intervention or limb amputation for PAD). The Fontaine classification was used for

Results

As of September 2005, a total of 1350 outpatients with symptomatic atherothrombotic disease had been enrolled in FRENA in 20 participating Spanish centers. One year later, 1265 (94%) had finished their 12-month follow-up. Of those who withdrew, 66 patients did so because of missed site visits and 19 because their enrolling physicians had withdrawn from the registry. Of the 1265 patients who finished, 417 (33%) had PAD (intermittent claudication 327, ischemia at rest 90); 474 (37%) had CAD

Discussion

The data in this analysis, obtained from a prospective series of consecutive patients in the FRENA registry, confirm that patients with PAD are at increased risk for major cardiovascular events during follow-up, independently of the presence of other covariates, such as patient's age, gender or underlying diseases. Furthermore, we found that this incidence increased with the severity of the symptoms, ranging from 8.7 events per 100 patient-years in patients in Fontaine stage IIa (intermittent

Learning points

Patients with PAD had an increased incidence of major cardiovascular events. Compared to patients with CAD or CVD they had a similar incidence of myocardial infarction or stroke, but a higher incidence of critical limb ischemia, limb amputation and death. This incidence increased with the severity of the symptoms of PAD.

Acknowledgements

We express our gratitude to S & H Medical Science Service for their logistic and administrative support. We thank Prof. Salvador Ortíz, Universidad Autónoma de Madrid and Statistical Advisor S & H Medical Science Service for the statistical analysis of the data presented in this paper.

We would like to thank Sanofi-Aventis for supporting this Registry with an unrestricted educational grant.

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Practice guidelines recommend that patients with peripheral artery disease receive antiplatelets, statins, and angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). We sought to quantify the rates of prescribing these therapies in patients with peripheral artery disease in the literature.
We performed a systematic review and meta-analysis of treatment prescribing rates in observational studies containing peripheral artery disease patients published on or after the year 2000. We also assessed whether prescribing rates are increasing over time.
A total of 86 studies were available for analysis. The aggregate sample size across all studies was 332,555. The pooled estimates for utilization of antiplatelets, statins, and ACE inhibitors or ARBs were 75% (95% confidence interval [CI], 71%-79%), 56% (95% CI, 52%-60%), and 53% (95% CI, 49%-58%), respectively. Statin use was directly related to publication year (+2.0% per year, P < .001), but this was not the case for antiplatelets (P = .68) or ACE inhibitors or ARBs (P = .066).
Although some improvement in statin prescribing has occurred in recent years, major practice gaps exist in the treatment of peripheral artery disease. Effective measures to close these gaps should be implemented.
Commentary on “Predictors of Change in the Ankle Brachial Index with Exercise”
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N-3 polyunsaturated fatty acids alleviate high glucose-mediated dysfunction of endothelial progenitor cells and prevent ischemic injuries both in vitro and in vivo
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Citation Excerpt :
Recent studies have suggested that peripheral artery diseases, such as critical limb ischemia (CLI), are frequently observed in diabetic patients [2,3]. Moreover, CLI is significantly associated with both CAD and ischemic stroke, which are major causes of mortality and disability in diabetic patients [4–7]. Furthermore, hyperglycemia is correlated with senescence of human endothelial progenitor cells (EPCs) and the occurrence of microvascular diseases in T2D patients [8].
Hyperglycemia is associated with a reduced number of endothelial progenitor cells (EPCs) that impairs vascular function. Circulating EPCs play important roles in postnatal neovasculogenesis and the prevention of ischemic injury. Frequent consumption of fish oil (FO) that is abundant with eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) is reportedly associated with an alleviation of diabetic complications and a lowered incidence of cardiovascular disease. The aim of this study was to examine whether N-3 polyunsaturated fatty acids such as EPA and DHA would reverse the high glucose-mediated dysfunction of EPCs in vitro and thereby prevent the ischemic injury that occurs under the hyperglycemic conditions in Type 2 diabetes (T2D) db^−/− mice. The results demonstrate that EPA and DHA alleviate high glucose-mediated impairment of tubular formation in EPCs through a rescue of neovasculogenic capability. The molecular mechanisms underlying the effects of EPA and DHA include the activation of the extracellular signal-regulated kinase 1/2, Akt/endothelial nitric oxide synthase (eNOS) and AMP-activated kinase (AMPK) signaling cascades as well as the phosphorylation of the downstream FOXO3a protein in EPCs. Moreover, EPA and DHA up-regulate the expression of c-kit, erythroid 2-related factor and heme oxygenase-1 proteins. Daily consumption of FO at dosages of 4% and 6% (wt/wt) significantly increased the level of bone marrow-derived and circulating EPCs, induced a recovery of blood flow and prevented ischemic injuries in a T2D db^−/− mouse model. The effects of FO consumption were exerted the activation of Akt/eNOS and AMPK signaling cascades without any effect on the plasma VEGF level in vivo.
Design and rationale for the Effects of Ticagrelor and Clopidogrel in Patients with Peripheral Artery Disease (EUCLID) trial
2016, American Heart Journal
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Estimates were made using the best available data. PAD subgroups were analyzed from prior trials [10,22,23] and registries [24–28]. Key variables used for event estimation included the proportion of subjects estimated to be enrolled with different ABI cutoffs, prevalence of polyvascular disease, and critical limb ischemia.
Despite overwhelming data demonstrating the efficacy of antiplatelet therapy in heart disease and stroke, data in peripheral artery disease (PAD) are less compelling. Aspirin has modest evidence supporting a reduction in cardiovascular events in patients with PAD, whereas clopidogrel monotherapy may be more effective in PAD. Ticagrelor, a potent, reversibly binding P2Y₁₂ receptor antagonist, is beneficial in patients with acute coronary syndrome and prior myocardial infarction. The EUCLID trial is designed to address the need for effective antiplatelet therapy in PAD to decrease the risk of cardiovascular events.
EUCLID is a randomized, double-blind, parallel-group, multinational clinical trial designed to evaluate the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events in subjects with symptomatic PAD. Subjects with established PAD will be randomized in a 1:1 fashion to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. The primary end point is a composite of cardiovascular death, myocardial infarction, or ischemic stroke. Other end points address limb events including acute leg ischemia, need for revascularization, disease progression by ankle-brachial index, and quality of life. The primary safety objective is Thrombolysis in Myocardial Infarction–defined major bleeding. Recruitment began in December 2012 and was completed in March 2014; 13,887 patients were randomized. The trial will continue until at least 1,364 adjudicated primary end points occur.
The EUCLID study is investigating whether treatment with ticagrelor versus clopidogrel, given as antiplatelet monotherapy, will reduce the incidence of cardiovascular and limb-specific events in patients with symptomatic PAD.
Peripheral artery disease and outcomes after myocardial infarction: An individual-patient meta-analysis of 28,771 patients in CAPRICORN, EPEHESUS, OPTIMAAL and VALIANT
2013, International Journal of Cardiology
Citation Excerpt :
Compared to those without, patients with PAD also have more biomarker evidence of inflammation and a pro-coagulant state [20]. Patients with PAD are often under-treated with secondary-preventive therapy, particularly beta-blockers [21–23] a finding confirmed in the present study. An observation not reported previously was the increased risk of heart failure hospitalization in our analysis.
To examine the prevalence of peripheral artery disease (PAD) and the relationship between PAD and cardiovascular (CV) outcomes in subjects with left ventricular systolic dysfunction, heart failure or both after acute myocardial infarction (MI).
PAD is associated with poorer prognosis in patients with stable and unstable coronary heart disease but whether PAD is associated with worse outcomes following substantial acute MI is unknown.
Univariate and multivariate Cox proportional hazards modelling was used to compare clinical outcomes in an individual-patient meta-analysis of 4 trials (CAPRICORN, EPHESUS, OPTIMAAL and VALIANT).
Of the 28,771 patients randomized, 2357 (8.2%) had PAD. These patients were older and had more co-morbidity and were less likely to be prescribed aspirin or a beta-blocker compared to patients without PAD. Over a mean follow-up of 2.7 years, 5121 (17.8%) patients died and 15,055 (52.3%) experienced CV death or hospitalization. PAD was an independent predictor of all individual and composite CV outcomes examined (including heart failure), with the exception of stroke. In patients with PAD (compared to those without PAD), the adjusted hazard ratio (HR) for all-cause mortality was 1.25 (95% CI 1.15–1.37; p < 0.001) and the HR for CV death, non-fatal MI, non-fatal stroke or heart failure hospitalization was 1.24 (1.16–1.33; p < 0.001).
PAD is common and is an independent predictor of worse outcomes in patients already at high risk after MI because of left ventricular systolic dysfunction, heart failure or both. These patients represent an important group for intensive application of secondary preventive therapies.
Association of foot ulcer with tibial artery calcification is independent of peripheral occlusive disease in type 2 diabetes
2013, Diabetes Research and Clinical Practice
Citation Excerpt :
It is thought that neuropathy, though its ability to decrease protective sensation, and arterial occlusion, though its resultant decrease in pedal perfusion, allow for the development and progression of ulcers to a point where complete healing is not possible. Another possibility that has been widely proposed is that calcification in lower extremity arteries increases ulcer risk through its association with atherosclerotic occlusive disease [8,19–23]. From this point of view, when arterial calcification is seen on X-rays, it can be viewed as a marker of extensive vascular occlusion.
To determine the relationship between foot ulcers, arterial calcification, and peripheral occlusive disease in patients with type 2 diabetes.
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There is a strong association between arterial calcification and diabetic foot ulcers that persists after adjusting for the extent of atherosclerosis in patients with type 2 diabetes.

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¹: A full list of FRENA investigators is given in the Appendix.

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Original articleClinical outcome in patients with peripheral artery disease. Results from a prospective registry (FRENA)

Abstract

Background

Patients and methods

Results

Conclusions

Introduction

Section snippets

Inclusion criteria

Results

Discussion

Learning points

Acknowledgements

Atherosclerosis

J Am Coll Cardiol

J Vasc Surg

Mortality over a period of 10 years in patients with peripheral arterial disease

N Engl J Med

Coronary artery disease in peripheral vascular patients. A classification of 1000 coronary angiograms and results of surgical management

Ann Surg

Ankle–arm index as a predictor of cardiovascular disease and mortality in the Cardiovascular Health Study. The Cardiovascular Health Study Group

Arterioscler Thromb Vasc Biol

Management of peripheral arterial disease (PAD) TASC Working Group. TransAtlantic Inter-Society Consensus (TASC)

J Vasc Surg

The prognosis of non-critical limb ischaemia: a systematic review of population-based evidence

Brit J Gen Pract

Original article
Clinical outcome in patients with peripheral artery disease. Results from a prospective registry (FRENA)