Impact of Prior Peripheral Arterial Disease and Stroke on Outcomes of Acute Coronary Syndromes and Effect of Evidence-Based Therapies (from the Global Registry of Acute Coronary Events) Debabrata Mukherjee, MD*, Kim A. Eagle, MD, Eva Kline- Rogers, MS, RN, Laurent J. Feldman, MD, Jean-Michel Juliard, MD, Giancarlo Agnelli, MD, Andrzej Budaj, MD, Álvaro Avezum, MD, PhD, Jeanna Allegrone, MS, Gordon FitzGerald, PhD, Philippe Gabriel Steg, MD, on behalf of the GRACE Investigators * Corresponding Author

Background Acute coronary syndrome (ACS) is a manifestation of global atherosclerosis and may be associated with atherosclerosis at other arterial sites The impact of prior PAD and stroke on outcomes in patients with an ACS has not been well studied Prior studies have demonstrated that combination evidence- based therapies including antiplatelet drugs, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and lipid- lowering drugs have proven efficacy in reducing mortality in patients with an ACS but the impact of the combination of these therapies in ACS patients with prior PAD or prior stroke has not been studied

Objectives Our objective was to assess the impact of prior PAD and stroke on in-hospital and intermediate- term clinical outcomes in patients with an ACS, and to ascertain the effectiveness of a combination of antiplatelet drugs, beta-blockers, ACE inhibitors and lipid-lowering drugs on intermediate-term outcomes using data from a large, ongoing, observational study

Methods Full details of the GRACE methods have been previously published ( GRACE is designed to reflect an unselected population of patients with ACS, irrespective of geographical region. A total of 113 hospitals located in 14 countries in North and South America, Europe, Australia and New Zealand have contributed data to this observational study

Methods PAD was defined as history of PAD documented in the medical record or history of claudication either with rest or exertion; amputation for arterial insufficiency; aorta-iliac occlusive disease reconstruction surgery; peripheral vascular bypass surgery, angioplasty, or stent; documented abdominal aortic aneurysm, aneurysm repair or stent; and documented positive non-invasive testing such as abnormal ankle-brachial index or pulse volume recording Transient ischemic attack was defined as history of loss of neurological function caused by ischemia that was abrupt in onset but with complete return of function within 24 hours; stroke or cerebral vascular accident was defined as loss of neurological function caused by an ischemic event with residual symptoms

Methods For each patient there were four possible recommended drugs: antiplatelet drugs, lipid-lowering therapy, ACE inhibitors, and beta-blockers A composite appropriateness score was calculated for each patient on the basis of the number of the drugs prescribed at discharge divided by the number of drugs indicated, expressed as a percentage Composite appropriateness level was determined for each patient according to the following algorithm: –appropriateness level 0: 0% of indicated medications used –appropriateness level I: 25% of indicated medications used –appropriateness level II: 50% of indicated medications used –appropriateness level III: 75% of indicated medications used –appropriateness level IV: 100% of indicated medications used.

Methods We compared death, myocardial infarction, stroke, and the composite of these outcomes in the various groups during hospitalization and at 6-month follow-up Stepwise multivariable logistic regression analysis was used to adjust for baseline demographics and comorbidities based on models described previously Furthermore, the impact of the composite appropriateness level on 6-month mortality and morbidity on ACS patients was analyzed using this risk-adjusted logistic regression model

Adapted from Mukherjee et al, Am J Cardiol 2007;100:1– 6 Results

Adapted from Mukherjee et al, Am J Cardiol 2007;100:1– 6 Results

Adapted from Mukherjee et al, Am J Cardiol 2007;100:1– 6 Results

Adapted from Mukherjee et al, Am J Cardiol 2007;100:1– 6 Results

Adapted from Mukherjee et al, Am J Cardiol 2007;100:1– 6 Results

Adapted from Mukherjee et al, Am J Cardiol 2007;100:1– 6 Results

Summary Atherosclerosis is a generalized process influenced by several important risk factors including tobacco smoking, diabetes, hypertension, and hyperlipidemia Patients with ACS often have concomitant PAD and cerebrovascular disease Patients with a previous atherothrombotic event at one site are at increased risk of mortality or morbidity from a recurrent event in the same or another vascular bed The present analysis, which is based on data from a large observational cohort study, demonstrates that clinical outcomes after ACS are worse in patients with prior history of either PAD or stroke, with the highest risk in patients with both conditions

Summary Moreover, these patients receive invasive and interventional therapies less frequently compared to patients without PAD or stroke These data suggest that higher total atherosclerotic burden with more diffuse atherosclerosis in different arterial distributions is associated with worse in-hospital and intermediate-term clinical outcomes

Summary Patients with ACS who have history of PAD and or stroke have, by definition, atherosclerosis in these extra-coronary distributions and may be at particularly high risk for plaque rupture at non-coronary arteries It would appear intuitive that evidence-based therapies should be effective in reducing cardiovascular morbidity and mortality in such high-risk patients This study demonstrates that use of combination evidence-based medical therapies (aspirin, beta-blockers, lipid lowering agents and ACE inhibitors) was independently and strongly associated with lower 6-month mortality and morbidity in patients with ACS across all subgroups Such therapies, most of which are generic and inexpensive today, appear to offer a marked advantage when compared with patients in whom such therapies are indicated but are omitted

Conclusions Atherosclerosis is a generalized process influenced by several important risk factors including smoking, diabetes, hypertension and hyperlipidemia Atherosclerosis may involve multiple arterial territories in addition to the coronary arteries Patients with ACS often have concomitant PAD and cerebrovascular disease. Patients with a previous atherothrombotic event at one site are at increased risk of mortality or morbidity from a recurrent event in the same or another vascular bed This analysis demonstrates that clinical outcomes after ACS are worse in patients with either PAD or stroke, with the highest risk in patients with both conditions The study further demonstrates that use of combination evidence-based medical therapies was independently and strongly associated with lower 6- month mortality and morbidity in patients with acute coronary syndromes

Acknowledgements The authors thank the physicians and nurses participating in GRACE Further information about the project, along with the complete list of participants, can be found at We are grateful to Sophie Rushton-Smith, PhD, who provided editorial support