The conundrum of ALI and systemic embolic events: SEEing our way to improved vascular health

The sudden disruption of arterial blood flow to any organ leads to tissue death. Acute ischemia is a vascular emergency. If flow is not promptly re-established, organ death – and often organism death – ensues. Acute limb ischemia (ALI) represents such an emergency. ¹

Atherothrombosis leading to the acute occlusion of a coronary artery (acute myocardial infarction or AMI) or occlusion of a cerebral artery (acute atherothrombotic stroke) are universally recognized as vascular emergencies. This was not always so. The causes, incidence, prevalence, acute treatment and natural history of these syndromes are now well defined. They are routinely ascertained in clinical trials using harmonized definitions endorsed by cardiovascular professional societies and health regulatory agencies. The accumulated evidence has led to the dissemination of therapies that modify disease incidence and are approved for clinical use. Acute treatment and strategies for secondary prevention are well understood by clinicians. Public health efforts have informed citizens to quickly recognize heart and stroke symptoms. Every health professional, clinic, hospital, and health system – supported by professional societies and state departments of health – can deliver expedited ‘systems of care’ in order to lower the morbidity and mortality of these vascular emergencies.

Acute limb ischemia is a vascular emergency that is at least as dangerous as stroke or heart attack. Nevertheless, current knowledge of the causes, incidence, natural history and prevention of ALI remains limited (Table 1). ALI was once considered a rare event. That perception is a myth, with rates exceeding that for stroke in at-risk populations. ALI can arise from local atherothrombotic mechanisms in patients with peripheral artery disease (PAD). Or, in patients with atrial fibrillation (AF), ALI represents one major systemic manifestation of a cardiac systemic embolic event (SEE), similar to stroke and acute infarction of other tissues (e.g. liver, kidney, spleen, intestines). The distinction in the etiology and secondary prevention of these two types of ALI is critical in caring for patients at risk for these devastating events.

Table 1.

Acute limb ischemia and systemic embolic event knowledge gaps: contrast with acute myocardial infarction.

Knowledge area	Acute myocardial infarction (AMI)	Non-embolic acute limb ischemia(ALI)	Systemic embolic events(SEE)
Etiology		‘Acute limb ischemia’ and ‘systemic embolic events’ are not identical terms, have diverse potential etiologies, and represent a spectrum of acute ischemic risk.
	Type 1 is atherothrombotic due to plaque rupture and thrombosis occluding a coronary vessel.Other types include demand (Type 2) and procedural MIs (Type 4, Type 5).	Atherothrombotic due either to plaque rupture and thrombosis occluding a peripheral vessel, or as an in situ stent or graft thrombosis.	Thromboembolic in the context of atrial fibrillation or any other cardiac source (e.g. LV, valvular). May also occur as an artery to artery embolic event (e.g. from atheroma or aneurysm).
Epidemiology
Population at risk1–3	Patients with atherosclerosis risk factors, or symptomatic atherosclerosis including CAD, cerebrovascular disease or PAD. Patients with prior MI are at heightened risk.	Patients with atherosclerotic PAD, particularly those with a history of prior limb arterial revascularization.	Patients with atrial fibrillation, particularly those with a high CHADS 2 VASC score. Other risk factors include aortic atherosclerosis, arterial aneurysms, or LV thrombus.
Incidence1,3,4	0.9% per year in the broad population with prior MI, stable CAD, PAD, or risk factors.1.75% per year in patients with CAD and prior MI.	1.3% per year in patients with symptomatic PAD and no atrial fibrillation, with ~60% having a history of leg arterial revascularization procedures.	0.6–5% per year as defined from different AF trial sources. This may decrease to 0.12% per year on warfarin and 0.08% per year on a direct oral anticoagulant.
Acute associated mortality from clinical trials2,3	<10%	12%	11–25%
1-year associated mortality from observational studies	10–20%	20–30%	35–45%
Other morbidity	Heart failure: 15%	Limb loss: 17% acutely	Limb loss: 5–12% acutely
Diagnosis
Published definition2,3,5	Universal definition of myocardial infarction.	In vascular specialty practice:Society for Vascular Surgery/International Society for Cardiac Vascular Surgery (SVS/ISCVS) severity classification.In clinical practice:The 5 or 6 P’s.Clinical trial definition: Acute ischemia with either a consistent clinical history and exam finding (pulse deficit with rest pain, pallor, paresthesia or paralysis) or direct confirmation (imaging, surgical, pathology).	Clinical trial definition: Clinical evidence of decreased perfusion with clinical or radiographic evidence of arterial occlusion unlikely to be caused by another mechanism.
Consistent ascertainment and definitions in clinical trials	YES	NO	YES, but variable
Treatment
Acute	Antiplatelet therapy, anticoagulant, reperfusion with fibrinolytic or percutaneous intervention.	Antiplatelet, anticoagulant or reperfusion (fibrinolytic or revascularization) therapies. If late presentation – amputation.	Antiplatelet, anticoagulant or reperfusion (fibrinolytic or revascularization) therapies. If non-viable limb – amputation.
Antithrombotic secondary prevention	Aspirin, P2Y12 inhibitor and/or PAR-1 antagonist (if P2Y12 is clopidogrel).	Aspirin, PAR-1 antagonist. P2Y12 inhibitor commonly used if peripheral stenting performed.	Systemic anticoagulation.
Knowledge dissemination
Epidemiology	YES	NO	NO
Acute treatment	YES	YES when recognized	YES when recognized
Secondary prevention	YES	NO	YES

AF, atrial fibrillation; CAD, coronary artery disease; LV, left ventricle; MI, myocardial infarction; PAD, peripheral artery disease.

ALI incidence and mortality versus clinical recognition

In describing rates of ALI, it is critical to characterize the etiology and population at risk. For example, Baril et al. evaluated the US Medicare population between 1998 and 2009 to document trends in the incidence of lower extremity ALI. ² They reported that ALI hospitalization rates decreased from 45.7 to 26.0 per 100,000 (p<0.001). In a recent analysis from a large clinical trial in patients with AF, the rate of SEE on anticoagulation was 0.12% per year (0.08% on a direct oral anticoagulant). ³ At the same time, clinical trials of secondary prevention strategies in patients with symptomatic PAD and no AF show ALI rates of 1.3% per year (more than 10-fold higher). Even within the data-enriched clinical trials context, estimates of ALI or SEE incidence and ascertainment of the benefits of treatments are not well defined. However, it is absolutely clear that the outcomes after ALI are poor, with a 12–13% immediate mortality and 15–20% short-term limb amputation risk.

Given these outcomes and the potential benefit of potent antithrombotic preventive therapies, it is difficult to understand why – until recently – ALI was ‘not observed’ in most cardiovascular trials. Many of these trials were truly ‘double blind’ as limb ischemic symptoms may not be routinely reported by patients nor systematically recognized by clinicians. While a number of trials have evaluated the efficacy of antiplatelet and anticoagulant regimens in patients with cardiovascular disease, including PAD, prospective ascertainment and adjudication of ALI has not been routinely performed. Recently, two large trials ascertained and adjudicated this endpoint, each showing robust reductions in this frequent and highly morbid event (vorapaxar, ticagrelor).^4–6 As well, ALI from systemic embolism in patients with atrial fibrillation, but without PAD, is also associated with poor outcomes. ⁷ These SEE constituted 11.5% of clinically recognized thromboembolic events, and was associated with a 25% 30-day mortality.

Further, contemporary outcomes after ALI were evaluated in a major tertiary care hospital in Minneapolis, a state with a low incidence of coronary heart disease and a low myocardial infarction case fatality rate. Amongst the 74 sequential ALI patients evaluated in the FRIENDS Registry between 2007 and 2009, and despite very high rates of use of risk reduction medications, 23% of the cohort was dead in 1 year, higher than that for MI or stroke. ⁸

Why we are blind

This is the conundrum: when patients and clinicians are not trained to recognize ALI or SEE, then steps required to improve the health impact are impaired. The ‘perceived’ low incidence of clinically important events creates little incentive to provide population-based surveillance and to implement preventive strategies. Near universal non-recognition of the acute limb risk associated with PAD – a risk that is as profound in its related disability and mortality as stroke – fosters a general sense of complacency about preventive intervention – claudication won’t kill you. In addition, the lack of routine recognition of the future systemic risk in patients presenting with embolic ALI may lead to under-utilization of well-proven preventive strategies (e.g. anticoagulation). The cycle of ALI ignorance is sustainable: Infrequent publication of insightful ALI clinical research does not inspire new research. The absence of an ALI clinical research infrastructure (investigators and data sources) impairs the success of junior investigators who might otherwise focus their careers on this clinical challenge. The ALI challenge, now recognized primarily by vascular surgeons, is a universal challenge to all practicing clinicians. While vascular surgeons usually serve in the front line of care for ALI, they cannot be held responsible, in isolation, for evaluation and implementation of methods to prevent this event in at-risk patients. It might be anticipated that cardiologists and vascular medicine specialists would be well positioned to assess the contributions of embolic, atherothrombotic, or other etiologies for these patients, and thus to define an optimal patient-specific preventive strategy.

The current study

This is the context in which Landry and colleagues at the Oregon Health and Science University studied the demographic and echocardiographic factors that predict sites of embolization, and that clarify current limb salvage and mortality rates for patients who suffer an ALI event. ⁹ This single-center case series evaluated 161 patients with symptomatic ALI due to cardiogenic emboli, of which 56 affected the upper extremity and 105 the lower extremity. The authors present a descriptive analysis of embolic limb events and not of atherothrombotic ALI occurring in patients with PAD.

A primary conclusion of their analysis is a differential female to male ratio of upper (70% vs 30%) versus lower extremity (47% vs 53%) events. In addition, Landry et al. report that atrial fibrillation was a more common cause of upper versus lower extremity ALI (50% vs 30%). Differential upper versus lower extremity limb salvage and 30-day survival rates were reported. The authors conclude that gender- and cardiac-specific differences in patterns of blood flow lead to preferential sites of peripheral embolization. While these observations are interesting and hypothesis generating, they need to be reproduced with better understanding of the causes, specifically for the difference in rates by gender.

As with prior studies of both atherothrombotic and embolic ALI, the most helpful metric is that of associated mortality. In this study, similar to others, mortality was high, with a third of patients dying at 1 year. The reader should be cautious in understanding that the associated mortality observed in patients with SEE may be due to systemic atherosclerotic events (MI or stroke) or co-morbid disease, rather than the SEE itself.

Overall this single-center observational study provides interesting data that hopefully will drive future investigation to define specific factors that might drive emboli preferentially into specific arterial beds. Of course, the primary health goal would be best achieved by efforts to identify the population at risk and then to prevent embolization and the associated morbid and mortal events. Perhaps more routine recognition of small or subclinical events and earlier implementation of therapies might prevent recurrent severe events.

Diagnostic algorithms, guidelines and real world care

While our professional societies have published ALI diagnostic and treatment guidelines, in truth no past investigation has been completed to assess the effectiveness of diagnostic strategies, such as the use of electrocardiogram (ECG) or rhythm monitoring and/or echocardiography. ¹⁰ It is possible that ideal care might not require any such testing to detect AF or a ‘cardiac source’: the first systemic embolic event could, of itself, inform a mandate for lifelong systemic anticoagulation.

Similarly, treatment strategies to prevent the first atherothrombotic ALI event in patients with symptomatic PAD are needed. The recent demonstration that a novel, first to market PAR-1 antagonist, vorapaxar, reduced ALI as a pre-defined outcome event and adjudicated in a double-blinded trial was a landmark, potentially practice-changing observation. A similarly effective antithrombotic strategy for ALI prevention has subsequently also been shown with the P2Y₁₂ inhibitor ticagrelor in patients with prior MI and PAD. Preventing ALI in high-risk populations should be as important as preventing other morbid ischemic events and, in fact, ongoing trials have now included ALI in their primary or key secondary endpoints along with MI and stroke.

Call for research

Knowledge is power. What is sure is that ALI incidence is higher than we recognize and that outcomes are frighteningly poor. Rational hope is achieved by clinical research that defines key knowledge gaps, provides data-driven answers, and creates knowledge and clinical parity for individuals who suffer an ALI event, that they might enjoy comparable benefits to those who suffer an MI (Table 1). One could now design a national multicenter ALI clinical registry capturing all etiologies. This would not be, in our opinion, consistent with the current wave of interest in specialty-specific registries that are not hypothesis-driven, with a narrow focus on distinct vascular diseases, or that accrue patients by individual vascular specialties. One could imagine a national Heart, Lung, and Blood Institute study designed to recruit and randomize subjects with ALI, applying distinct diagnostic or therapeutic strategies to inform measurement of their incremental clinical value. One could evaluate the effectiveness of hypercoagulable testing to inform the intensity of anticoagulation. One could evaluate the relative benefit, harm, and cost-effectiveness of vitamin K antagonist, direct oral anticoagulant, or antiplatelet medications on recurrent event rates and mortality.

Call to action

We need to do better. Vascular medicine is quality cardiovascular medicine. If we do not recognize systemic embolic events, then we SEE no evil, study no evil, and cannot prevent these morbid and mortal acute arterial events. The work of Landry et al. helps us open our eyes. ALI is the iceberg ahead. Patients are at risk. Ignorance is not bliss. Ignorance is death. The idea that acute limb ischemia is benign is not truth, but is – in fact – ALI.