Antithrombotic Treatment for Peripheral Arterial Occlusive Disease
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Background: Patients with peripheral arterial occlusive disease (PAOD) are at elevated risk for cardiovascular events and vascular events affecting the limbs. The goals of antithrombotic treatment are to keep vessels open after revascularization, to prevent cardiovascular events, and to lessen the frequency of peripheral ischemia and of amputation.
Methods: This review is based on pertinent publications retrieved by a selective literature search, with particular attention to meta-analyses, randomized controlled trials, and the German and European angiological guidelines.
Results: Diabetes mellitus and nicotine abuse are the main risk factors for lower limb PAOD. The evidence for the efficacy and safety of antithrombotic treatment in patients with PAOD is limited, in particular, after surgical or endovascular revascularization. Intensifying antithrombotic treatment with stronger antiplatelet therapy (APT), dual antiplatelet therapy (DAPT), or antiplatelet therapy combined with anticoagulation lowers the rate of peripheral revascularization (relative risk [RR] 0.89; 95% confidence interval [0.83; 0.94]), amputation (RR 0.63; [0.46; 0.86]), and stroke (RR 0.82; [0.70; 0.97]) but raises the risk of bleeding (RR 1.23; [1.04; 1.44]). Predictors for peripheral vascular events include critical limb ischemia and having previously undergone a revascularization procedure or an amputation.
Conclusion: Antiplatelet therapy should only be intensified for a limited time, or if the risk of ischemia is high. Before and during intensified antiplatelet therapy, the risk of bleeding should be assessed and weighed against the risk of ischemia. No validated score is available to estimate the risk of hemorrhagic complications in patients with PAOD. New antithrombotic therapies should not be used indiscriminately, but should rather be reserved for selected groups of patients.
The importance of peripheral arterial occlusive disease (PAOD) is growing by virtue of its increasing incidence. Furthermore, recently published studies have drawn attention to the poor prognosis of patients with PAOD with regard to vascular events affecting the limbs as well as cardiovascular events.
In Germany, the number of PAOD-related hospitalizations rose by 20.7% between 2005 and 2009 (2005: 400 928 of 15 million hospitalizations [2.67%]; 2009: 483 961 of 16.2 million [3.0%]). These figures included a disproportionate increase (32%) in the number of patients with advanced (Fontaine stage IV) disease (1).
Chronic critical limb ischemia (CLI) is associated with a poor prognosis. A systematic review found higher overall mortality (relative risk [RR] 2.26, 95% confidence interval [1.77; 2.89]) and a higher rate of amputation above the ankle (major amputation) (RR 3.85 [2.52; 5.87]) in patients with CLI than in patients with a lowered ankle-brachial index (2). After a major amputation, only 18–39% of patients with a prosthesis could walk around their household (3). A meta-analysis of predominantly retrospective cohort studies found 1-year mortality of 24–48% (4). Major adverse limb events (MALE) comprise:
- Acute limb ischemia (ALI)
- Chronic limb ischemia that results in revascularization or hospitalization
- Major amputation for vascular reasons
By 2 years after ALI, 27% of patients had needed an amputation and 12% had died (5).
Registry studies have revealed that patients with PAOD are often undertreated. In the REACH registry (patient inclusion 2003–2004), the cardiovascular risk factors in patients with PAOD were not controlled as well as in patients with cerebral arterial occlusive disease (CAOD) or coronary heart disease (CHD) (6). In a recent systematic review of randomized controlled studies (RCT) and observation studies, 92% of the patients with PAOD received antiplatelet therapy and 67% were given a statin (2).
Simultaneous manifestation of atherosclerosis in multiple vascular regions (CHD, CAOD, PAOD), termed polyvascular atherosclerosis, is associated with a higher risk of major adverse cardiovascular events (MACE). The EUCLID study found that the risk of MACE was 50% higher in patients with PAOD and accompanying CHD than in those with PAOD alone (8.9% versus 15.3%; hazard ratio [HR] 1.50 [1.13; 1.99], p = 0.005) (7), while in the PEGASUS-TIMI-54 study the risk was 60% greater in patients with PAOD who had suffered a myocardial infarction (HR 1.60 [1.20; 2.13], p = 0.0013) (8).
Antithrombotic treatment comprises administration of antiplatelet therapy (APT) and anticoagulants. As shown in a recent meta-analysis of RCT, intensification of antithrombotic treatment leads to reductions in the rates of amputation (RR 0.63 [0.46; 0.86]) and peripheral revascularization (RR 0.89 [0.83; 0.94]) over a 24-month period compared with APT alone. The stroke rate was lowered (RR 0.82 [0.70; 0.97]), but the risk of myocardial infarction was not decreased (RR 0.98 [0.87; 1.11]). The intensification, comprising combination of an anticoagulant and APT, dual antiplatelet therapy (DAPT), or an alternative form of APT, led to a significant increase in major bleeding events (RR 1.23 [1.04; 1.44]) (9).
The dual aim of this review is to show how patients with a high risk of ischemia can be identified and also to present the contradictions to intensified antithrombotic treatment. We investigate what form of antithrombotic treatment is indicated following revascularization and examine the application of new treatment protocols and the associated practical restrictions on daily life (Table 1).
The guideline recommendations of the relevant European and German professional societies are critically reviewed (10, 11, 12, 13, 14). Moreover, the PubMed database was searched for systematic reviews, meta-analyses, and RCT using the keywords “peripheral artery/arterial disease” and “antithrombotic therapy” or “anticoagulation” or “antiplatelet.” Studies of primary prevention and treatment of ALI were excluded from analysis.
Antithrombotic treatment is one of the cornerstones of conservative treatment of PAOD. The relevant German clinical practice guideline recommends inhibition of platelet aggregation with acetylsalycylic acid (ASA) or clopidogrel for secondary prevention of cardiovascular events (12). The guidelines of the British National Institute for Health and Care Excellence (NICE) and the European Society of Cardiology prefer clopidogrel to ASA (10, 13). The CAPRIE study showed that clopidogrel was superior to ASA with regard to MACE risk reduction (RR 0.76 [0.64; 0.91]), although the finding resulted only from a subgroup analysis and the absolute risk reduction (ARR) was low (ARR 1.2 %, number needed to treat [NNT]) 87 over 3 years) (15). The recommendation of the German clinical practice guideline, in which there is no general preference for clopidogrel, is thus comprehensible.
Symptomatic PAOD exists in the presence of intermittent claudication, pain at rest, or an ulcer or gangrene (12). There is no consensus on whether to use APT in asymptomatic PAOD. The German guideline highlights the lack of evidence, but justifies its recommendation of APT by reference to the high rate of accompanying silent CHD. The ESC guideline recommends no APT for asymptomatic PAOD, pointing to the lack of evidence and the elevated bleeding risk (10, 12). A recently published meta-analysis showed a minor clinical benefit only for non-fatal stroke (reduction of 5 events per 1000 patients [0; 8], p = 0.055), with a significantly elevated risk of major bleeding (increase of 4 events per 1000 patients [1; 8], p = 0.009) (16). These new data support the ESC recommendation not to use APT in asymptomatic PAOD.
In a network meta-analysis, DAPT with clopidogrel and ASA led to no significant reduction in MACE compared with ASA treatment, but increased significantly the risk of bleeding (RR 2.29 [1.58; 3.44]). There was an isolated finding of a non-significant trend towards a lower amputation rate with DAPT (RR 0.68 [0.43; 1.04]) (17).
The EUCLID study compared ticagrelor and clopidogrel for single-agent treatment of PAOD. Neither drug proved superior with regard to the risk of MACE (HR 1.02 [0.92; 1.13], p = 0.65) or ALI (HR 1.03 [0.79; 1.33], p = 0.85), and neither had a significant effect on the rate of major bleeding (HR 1.10 [0.84; 1.43], p = 0.49) (18). Ticagrelor is currently not licensed for the treatment of PAOD in Germany.
Treatment with a combination of low-dose rivaroxaban (2 × 2.5 mg/day) and ASA (100 mg/day) is recommended for PAOD patients without high bleeding risk or other complications in the guidelines of the European Society of Vascular Medicine (ESVM) (11). The NICE guidelines recommend this form of treatment for patients with a high risk of ischemia, provided the bleeding risk is determined, benefits and risks are analyzed and discussed with the patient, and regular re-evaluation takes place (14).
In the randomized placebo-controlled COMPASS study, combination treatment with low-dose rivaroxaban and ASA reduced the relative risk of MACE in PAOD patients by 28% (HR 0.72 [0.57; 0.90], p = 0.0047) compared with ASA alone, with an ARR of 1.9% and an NNT of 53 over 21 months.
The relative MALE risk was reduced by 46% (HR 0.54 [0.35; 0.82], p = 0.0037) although the ARR was low, at 1.1% (NNT = 90) (19). In the COMPASS study, a predefined subgroup analysis found that Fontaine stage III or IV (multivariate HR 4.79 [2.99; 7.69], p < 0.0001) and prior revascularization (multivariate HR 2.44 [1.71; 3.50], p < 0.0001) or amputation (multivariate HR 3.77 [2.40; 5.93], p < 0.0001) were predictors of MALE.
The combination treatment resulted in a significant increase of 1.2% in the absolute number of major bleeding events (HR 1.61 [1.12; 2.31], p = 0.0089, number needed to harm = 85) (20).
The NICE recommendation on this combination therapy is more complex, in that besides benefit/risk assessment, it includes patient adherence and stipulates regular re-evaluation.
The antithrombotic treatment following endovascular or surgical revascularization is described in the eMethods, while Table 2 provides orientation regarding antithrombotic treatment of lower-limb PAOD.
PAOD and diabetes mellitus
Diabetes mellitus is one of the most important risk factors for the development of PAOD. The extent to which diabetes worsens the prognosis of PAOD patients is frequently underestimated: the 5-year survival rate for ischemic diabetic foot syndrome is 50% (21).
Analysis of real-world data from a German health insurance provider revealed higher mortality and a higher amputation rate among 21 197 hospitalized patients with PAOD and diabetes than in PAOD patients without diabetes (HR 1.26 versus 2.238, p < 0.001). These risks were higher again in the additional presence of CHD (HR 2.19 versus 1.76, p < 0.001) (22).
Only 25% of patients with diabetes and PAOD notice clinical symptoms due to concomitant neuropathy, so the PAOD is first recognized at the stage of critical limb ischemia or diabetic foot syndrome (23).
In the POPADAD study, APT in patients with diabetes and asymptomatic PAOD yielded no benefit with regard to MACE, major amputations, and critical limb ischemia (HR 0.98 [0.76; 1.26]) (15). Therefore, the presence of diabetes does not influence the recommendation not to perform APT in asymptomatic PAOD.
The joint guideline of the ESC and the European Association for the Study of Diabetes (EASD) recommends the combination of low-dose rivaroxaban and ASA for patients with diabetes and PAOD who are not at high risk of bleeding (24). In a position paper of the German Diabetes Society (Deutsche Diabetesgesellschaft), the German Society for Angiology (Deutsche Gesellschaft für Angiologie), and the German Society for Interventional Radiology (Deutsche Gesellschaft für Interventionelle Radiologie), this treatment is recommended only for patients with diabetes who are at high risk of ischemic events (23).
A predefined subgroup analysis in the COMPASS study showed comparable relative risk reductions for the primary endpoint (cardiovascular death, myocardial infarction, or stroke) for patients with diabetes HR 0.74 [0.61; 0.90], p = 0.002; ARR 2.3%) and those without diabetes (HR 0.77 [0.64; 0.93], p = 0.005; ARR 1.4%). The bleeding events were also comparable (HR 1.70 [1.25; 2.31], p = 0.0006 versus HR 1.69 [1.33; 2.15], p < 0.0001). The higher ARR resulted in a lower NNT of 44 for patients with diabetes versus 73 for patients without diabetes over a period of 3 years (25).
The ESC/EASD recommendation seems more generous than the German position paper, because it does not take the risk of ischemia into account.
Treatment in the presence of alternative indications for anticoagulation
PAOD is often accompanied by atrial fibrillation, particularly in the elderly. In the REACH registry, 10% of the patients with symptomatic PAOD had atrial fibrillation (6). The evidence for the efficacy and safety of antithrombotic treatment in this scenario is limited. The combination of anticoagulation and APT significantly increases the risk of bleeding. In a Danish registry study, the risk of severe hemorrhage was increased by 50% (HR 1.50 [1.23; 1.82]) and 84% (HR 1.84 [1.11; 3.06]), respectively, by treatment with ASA or clopidogrel in addition to anticoagulation (26).
In the ESC guideline, usually no accompanying APT is recommended for patients with indications for anticoagulation. Only if the risk of ischemia is high can combination treatment with anticoagulants and APT be considered. By definition, the ischemia risk is high with prior stent thrombosis or ALI, as well as in the presence of a cardiological indication for APT (10).
After endovascular revascularization, the bleeding risk should be weighed against the risk of limb ischemia in the event of vascular occlusion. If the bleeding risk is high, anticoagulation alone is indicated. If both the risk of bleeding and the risk of ischemia are low, the accompanying APT should be stopped after 4 weeks and anticoagulation continued alone. In the case of low bleeding risk and high ischemia risk, one can consider prolonging combination therapy (10).
A meta-analysis of RCT showed that in PAOD patients with atrial fibrillation, the efficacy of non-vitamin-K-antagonist oral anticoagulants (NOAC) resembles that of warfarin for the MACE endpoints (27):
- Stroke (RR 0.93 [0.61; 1.42])
- Myocardial infarction (RR 1.10 [0.64; 1.90])
- Death from any cause (RR 0.91 [0.70; 1.19])
- Major bleeding (RR 1.12 [0.70; 1.81])
- Intracranial hemorrhage (RR 0.54 [0.16; 1.85])
Assessment of risk of bleeding versus ischemia
Antithrombotic treatment is inherently associated with an elevated risk of bleeding, so the danger of ischemia must be assessed in each individual case. Alongside the cardiovascular risk, there is also the extremity-related risk of ischemia, with the prognostically relevant endpoint of major amputation.
No validated score exists for assessment of the bleeding risk in PAOD, so individual criteria have to be considered. The situation is aggravated by the fact that some factors (e.g., age and renal failure) increase both the risk of bleeding and the danger of ischemia (28). The Box contrasts the criteria.
The offsetting of safety and efficacy endpoints in clinical studies as clinical net benefit is questionable in practice: gastrointestinal (GI) bleeding events, unlike cerebral apoplexy, myocardial infarction, or amputation, are frequently not associated with permanent impairment, and the risk of GI bleeding during DAPT can be lowered with a proton pump inhibitor (11, 29). In contrast, more weight should be attached to increased risk of intracranial or intraocular bleeding or hemorrhagic stroke because of the irreversible damage they often entail. In patients who are predisposed to such events, the treatment of arterial hypertension or diabetes should be optimized (30, 31). The Figure shows a proposed algorithm for use in daily routine.
Limitations and critical evaluation
For many years the recommendations regarding antithrombotic treatment of PAOD were based on conclusions drawn by analogy with CHD treatment or subgroup analyses from cardiological studies. More PAOD research is needed, especially exploring new options for antithrombotic treatment.
Most of the 128 recommendations in the ESC guidelines have evidence level C; only 20 recommendations feature evidence level A (10).
Licensing studies for medical products often differ in the type and duration of antithrombotic treatment (32). A standardized scheme is needed to minimize confounding effects.
It remains unclear whether the strategy of combining low-dose rivaroxaban and ASA can be extended to other membes of the NOAC group of substances. There has also been no comparison with clopidogrel monotherapy. The exclusion criteria applied in studies of combination treatment (especially elevated bleeding risk) mean that their results cannot be transferred unreservedly to routine practice (33). For example, combination therapy is contraindicated in the presence of (34):
- Status post hemorrhagic or lacunar stroke or stroke (of any cause) in the previous month
- Severe renal failure (creatinine clearance < 15 mL/min)
- Acute, clinically relevant bleeding events
- Lesions or situations involving risk of severe bleeding
The COMPASS study was terminated prematurely because the combination therapy was beneficial. The mean observation period was therefore only 23 months. No long-term real world data are yet available for this treatment option. Regular re-evaluation capable of capturing temporary changes in bleeding risk and renal function is thus advisable.
Assessment and clinical implications
Patients with PAOD are at high risk of ischemic events. Use of the term “stable PAOD” induces a false sense of security. Cardiologists have revised their terminology for this very reason: they now speak of “chronic coronary syndrome” rather than “stable CHD.” Analogously, the term “chronic” PAOD is more apposite and better respects the reduced prognosis of these patients.
Antithrombotic treatment for asymptomatic PAOD cannot be recommended, because there is no evidence of clinical benefit but the risk of bleeding is elevated. This also applies to patients with diabetes mellitus.
The preference for clopidogrel over ASA is based mainly on the statistically controversial subgroup analysis in the CAPRIE study and is also questionable in view of the low absolute reduction in risk (NNT = 87 over 3 years).
On benefit–risk analysis of intensified antithrombotic treatment, the following parameters suggest elevated risk of ischemia:
- Comorbidities (including diabetes mellitus, renal failure, and heart failure)
- Extend of atherosclerosis (polyvascular atherosclerosis)
- Prior ischemic events (Fontaine stage III/IV, status post revascularization or amputation)
The last-named are predictors of peripheral ischemic events and should prompt the question of whether it is necessary to intensify the antithrombotic treatment. Patients with high risk factors are those who will probably have the highest absolute benefit (14).
Treatment with a combination of low-dose rivaroxaban and ASA reduces rates of MACE and MALE, so this option should be considered in cases of high ischemia risk and low bleeding risk.
There are no standardized specifications for the regular re-evaluation of antithrombotic treatment. In our opinion, it is advisable to review the situation 4 weeks after the commencement of intensified treatment and then at least 6-monthly as well as after any bleeding events. The intervals should be shorter for patients with renal failure, advanced age, and comorbidities.
DAPT can usually be ended 4 weeks after revascularization, as can accompanying APT in cases where anticoagulation is indicated.
Before any escalation of secondary prevention drug therapy, all non-pharmacological measures, such as cessation of smoking and exercise therapy, should be exhausted. Optimal control of the cardiovascular risk factors should be a precondition.
Intensification of antithrombotic treatment has the potential to prevent ischemic events, but each individual case must be judged on its merits. This form of treatment is not suitable for all patients with PAOD.
Conflict of interest statement
Dr. Hardung has received consultancy fees from Bayer Vital GmbH and lecture honoraria from Bristol-Myers Squibb, Pfizer, and Bayer Vital GmbH.
Dr. Behne has received lecture honoraria from Bayer Vital GmbH.
Dr. Langhoff has received consultancy fees from Bayer Vital GmbH.
The remaining authors declare that no conflict of interest exists.
Manuscript submitted on 17 October 2020, revised version accepted on 16 February 2021
Translated from the original German by David Roseveare
Dr. med. David Hardung
Abteilung für Angiologie
Paretzer Str. 12, 10713 Berlin, Germany
Cite this as
Hardung D, Behne A, Boral M, Giesche C, Langhoff R: Antithrombotic treatment for peripheral arterial occlusive disease. Dtsch Arztebl Int 2021; 118: 528–35. DOI: 10.3238/arztebl.m2021.0157
University Hospital for Angiology, Brandenburg Medical School Theodor Fontane, Campus Hospital Center Brandenburg an der Havel: Dr. med. Ralf Langhoff
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