Antithrombotic therapy following revascularization for chronic limb-threatening ischaemia: a European survey from the ESC Working Group on Aorta and Peripheral Vascular Diseases

Abstract

Aims

Chronic limb-threatening ischaemia (CLTI) entails dismal outcomes and is an absolute indication to lower extremity revascularization (LER) whenever possible. Antithrombotic therapy is here crucial, but available evidence on best strategies (choice of drugs, combinations, duration) is scarce. We conducted a European internet-based survey on physicians’ use of antithrombotic therapy after revascularization for CLTI, under the aegis of the ESC Working Group on Aorta and Peripheral Vascular Disease in collaboration with other European scientific societies involved in CLTI management and agreeing to send the survey to their affiliates.

Methods and results

225 respondents completed the questionnaire. Antithrombotic therapy following surgical/endovascular LER varies widely across countries and specialties, with dedicated protocols reported only by a minority (36%) of respondents. Dual antiplatelet therapy with aspirin and clopidogrel is the preferred choice for surgical (37%) and endovascular (79%) LER. Dual pathway inhibition (DPI) with aspirin and low-dose rivaroxaban is prescribed by 16% of respondents and is tightly related to the availability of reimbursement (OR 6.88; 95% CI 2.60–18.25) and to the choice of clinicians rather than of physicians performing revascularization (OR 2.69; 95% CI 1.10–6.58). A ≥ 6 months-duration of an intense (two-drug) postprocedural antithrombotic regimen is more common among surgeons than among medical specialists (OR 2.08; 95% CI 1.10–3.94). Bleeding risk assessment is not standardised and likely underestimated.

Conclusion

Current antithrombotic therapy of CLTI patients undergoing LER remains largely discretional, and prescription of DPI is related to reimbursement policies. An individualised assessment of thrombotic and bleeding risks is largely missing.

Graphical Abstract

We conducted a European survey to appraise on the current use of antithrombotic therapies after revascularization for chronic limb-threatening ischaemia. A total of 225 centres responded to a web-based questionnaire documenting the choice of antithrombotic therapies regimens, and the use of intensified antithrombotic therapies after revascularization, either endovascular or surgical. Results of this survey document the heterogeneity of antithrombotic approaches and highlight the several unmet needs in this area.

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INTRODUCTION

Chronic limb-threatening ischaemia (CLTI) is a severe disease characterised by unrelenting limb pain, poor quality of life, and a high risk of limb amputation.^1,2 CLTI is also characterised by an extremely high risk of major adverse cardiovascular events (MACEs), comprising cardiovascular death, myocardial infarction and stroke. Historically, CLTI patients have been managed by physicians of different specialties, including vascular surgeons, vascular medicine specialists and cardiologists, with relevant differences within Europe. Such variability, together with the poor awareness of lower extremity arterial disease (LEAD)³ and with a paucity of randomised trials, has led to major disparities in management and clinical outcomes.

CLTI is an absolute indication to lower extremity arterial revascularization (LER), either surgical or endovascular. After endovascular LER, current guidelines recommend dual antiplatelet therapy (DAPT) with aspirin and clopidogrel for at least one month,^1,2 often extended to 3–6 months in clinical practice.⁴ Single antiplatelet therapy (SAPT) is recommended following surgical LER, while DAPT for up to 24 months is proposed for patients undergoing infrainguinal prosthetic bypass surgery.²

Recently, the ‘Vascular Outcomes studY of Aspirin alonG with rivaroxaban in EndovasculaR or surgical limb revascularization for peripheral artery disease’ (VOYAGER-PAD) trial demonstrated the efficacy of a novel regimen of low-dose rivaroxaban and low-dose aspirin—‘dual pathway inhibition’ (DPI)—in patients undergoing LER, independent of revascularization modality.⁵ Since the publication of this trial, the heterogeneous reimbursement criteria for DPI across Europe have further increased variability in the treatment of CLTI. Importantly, DPI has been proposed as the default strategy for both endovascular and surgical LER by the 2021 Consensus Document on antithrombotic therapies in aortic and peripheral arterial diseases authored by the ESC Working Group on Aorta and Peripheral Vascular Diseases (WG A&PVD) in collaboration with the Working Groups on Thrombosis and Cardiovascular Pharmacotherapy.⁶

Following its publication, the ESC WG A&PVD promoted a survey on AT in patients undergoing infrapopliteal LER for CLTI in collaboration with various European and National scientific societies across Europe, according to its mission of promoting collaboration among different specialties taking care of patients with vascular diseases.⁷ We hereby present the results of this survey.

METHODS

We designed a web-based questionnaire to obtain a photograph of the type and duration of AT prescribed by European specialists to CLTI patients undergoing surgical or endovascular revascularization of infrapopliteal arteries, isolated or associated with above-the-knee revascularization (Supplementary Annex S1). We also investigated the choice of AT in patient at high bleeding risk and in those with a compelling indication for oral anticoagulants (OAC). Additional information collected included an estimate of the number of infrapopliteal revascularization procedures performed at the respondents’ hospitals, and the presence of therapeutic protocols. The survey was in English and designed to be completed in <10 min. An e-mail invitation to complete the questionnaire was sent to 500 members of the WG A&PVD on 14^th May , 2021, and a link to the survey was published on the WG web page. In addition, the link was also published on the web pages of the European Society for Vascular Medicine and of the European Society for Vascular and Endovascular Surgery. Finally, an e-mail invitation to solicit response to the survey was sent to all the members of the National Societies of Vascular Surgery of Austria, Denmark, Italy, and Switzerland, the National Society of Angiology of Germany, and the National Societies of Vascular Medicine of Austria and Switzerland. The survey was closed on 27 June 2021.

Categorical variables were expressed as frequency and percentages. Assuming that SAPT with aspirin is the standard therapy in current clinical practice, we performed a multivariable logistic regression analysis to identify predictors of use of alternative therapies (DPI, DAPT, SAPT with clopidogrel), and of a longer duration of the intensified postprocedural AT (defined as any association of two or more antithrombotic drugs), both for surgical and endovascular revascularization, including all variables featuring a P < 0.10 at univariable analysis into the model. A significance level of P < 0.05 was required for a variable to be retained in the model. A two-sided P < 0.05 was considered statistically significant. All analyses were performed using the SAS version 9.4 statistical software (SAS Institute, Inc., Cary, NC, USA).

RESULTS

A total of 268 specialists responded to the questionnaire. Of these, 23 did not complete the survey, and 22 declared they did not work in a centre performing revascularization. Therefore, we collected a complete questionnaire from a total of 225 physicians from 17 European countries (n = 215; 95.6%) and six non-European countries (n = 10; 4.4%; these received the invitation as members of the WG A&PVD). Among European responders, 74.0% were from Western Europe, 16.3% from Southern Europe, 7.0% from Northern Europe, and 2.8% from Eastern Europe (Figure 1 and Supplementary material online, Table S1). Most responders (44.0%) were specialists in vascular medicine, 38.2% were vascular surgeons, 16.0% cardiologists, and the remaining 1.8% radiologists or internists (Figure 1). In the respondents’ hospitals, endovascular and surgical revascularization were performed in 96.8 and 87.1%, respectively, with 13.6% of the centres performing endovascular revascularization only. At the time of this survey, DPI was reimbursed only in Denmark, Germany, and Switzerland.

Most respondents reported that AT following revascularization is decided by physicians performing revascularization (77.3%), rather than by clinicians in charge of patients during hospitalization (20.4%)—if different from the one performing revascularization—, or the local Vascular Team (2.2%). On the other hand, a decision to de-escalate AT during follow-up was taken by physicians performing revascularization in a lower percentage (54.2%), with a larger role for clinicians in charge of patients during hospitalization (20.4%), specialists in charge of patients’ follows-up (21.4%) and general practitioners (4.0%) (Figure 2).

The existence of a dedicated written protocol for AT following revascularization was reported by 36.0% of the respondents, while an informal protocol was reported by 42.2% and no protocol by 21.8% (Figure 2). The assessment of bleeding risk in these patients was based on clinical judgement according to 72.3% of respondents, while bleeding scores were used by 27.7%.

Surgical revascularization

Among the 196 respondents working in centres performing surgical revascularization, the median of the reported monthly range of procedures was 11–20, with 25.0% operating >20 patients (high-volume centres). The routine postprocedural regimen was DAPT with aspirin and clopidogrel for 36.6% of respondents, SAPT for 20.9% (aspirin 16.3%, clopidogrel 4.6%), DPI for 13.7%, SAPT associated with short-term (1–6 months) LMWH for 15.7%, and full-dose OAC (either vitamin K-antagonists or direct oral anticoagulants) for 13.1% (short-term for 9.8%, long-term for 3.3%) (Figure 3). Prescription of DPI was associated with high-volume centres (23.7% vs. 10.8%, P = 0.049), as well as the presence of a written antithrombotic protocol (21.1%vs. 9.4%, P = 0.040), the choice of therapy by the clinician rather than by the surgeon (23.7%vs. 10.4%, P = 0.040), and the availability of reimbursement (25.4% vs. 6.4%, P = 0.0009). At multivariable analysis, the availability of reimbursement was the only independent predictor of DPI usage [odds ratio (OR) 3.80; 95% confidence interval (CI) 1.33–10.87]. Among the 79.1% of respondents reporting an intensified postprocedural regimen, duration of the initial antithrombotic regimen was 1 month for 13.3%, 3 months for 36.7%, 6 months for 19.2%, and ≥ 1 year for 30.8% of them (Figure 3).

The proportion of patients deemed at high bleeding risk was reported to be < 15% by 45.0% of respondents, 15–30% by 32.9%, and > 30% by 22.1%. The routine postprocedural AT for those patients was generally less intense, with SAPT for 67.1% (aspirin 44.1%, clopidogrel 23.0%), SAPT and short-term LMWH for 11.2%, DAPT for 9.9%, DPI for 6.6%, and OAC for 5.3% (short-term 4.0%, long-term 1.3%). According to the 32.9% of respondents describing an early intensified postprocedural AT, de-escalation to SAPT was prescribed earlier in high-risk than in non-high bleeding risk patients (de-escalation occurring at 1 month for 39.6% of respondents, at 3 months for 33.3%, at 6 months for 6.3%, and at ≥ 1 year for 20.8% of them).

Finally, among patients with concomitant indication for OAC, the routine postprocedural antithrombotic regimen was OAC associated with short-term SAPT (1–6 months) for 60.9% (aspirin 43.7%, clopidogrel 17.2%), OAC monotherapy for 35.8%, OAC associated with long-term aspirin for 2.7%, and DAPT without OAC for 0.7%.

Endovascular revascularization

The 218 respondents working in centres performing endovascular revascularization reported a median monthly range of endovascular procedures of 11–20, with 41.5% treating >20 patients per month. The routine postprocedural AT was DAPT for 79.2% of respondents, DPI for 11.6%, SAPT associated with short-term LMWH for 5.2%, SAPT for 2.9% (aspirin 2.3%, clopidogrel 0.6%), and short-term OAC for 1.1% (Figure 4). Prescription of DPI was associated with choice by a clinician rather than the interventionist (22.7% vs. 7.8%, P = 0.007), and with reimbursement availability (27.5% vs. 1.0%, P < 0.0001). Reimbursement availability (OR 37.0; 95% CI 4.8–286) and choice by a clinician (OR 3.1; 95% CI 1.05–8.84) were independent predictors of DPI usage. Among the 97.1% of respondents reporting a postprocedural regimen more intense than SAPT, duration of intensified AT was 1 month for 18.5%, 3 months for 45.2%, 6 months for 19.6%, and ≥ 1 year for 16.7% (Figure 4).

Among recipients of endovascular procedures, the proportion of patients deemed at high bleeding risk was reported to be < 15% by 41.7% of respondents, 15–30% by 34.5%, and > 30% by 23.8%. The preferred postprocedural antithrombotic regimen for those patients was SAPT for 53.5% (aspirin 25.6%, clopidogrel 27.9%), DAPT for 30.2%, SAPT and short-term LMWH for 8.7%, DPI for 6.4%, and OAC for 1.1%. Among the 46.5% of respondents reporting an initial intensified postprocedural regimen, the duration of such regimen was 1 month for 52.6%, 3 months for 29.2%, 6 months for 10.2%, and ≥ 1 year for 8.0%.

The preferred postprocedural AT for patients with concomitant indication for OAC was OAC with short-term SAPT for 77.1% (aspirin 42.4%, clopidogrel 34.7%), and OAC monotherapy for 22.9%.

Overall revascularization analyses

When considering AT for combined surgical and endovascular revascularization, the prescription of DPI (15.9% of responders) tended to be associated with the presence of a written antithrombotic protocol (21.7% vs. 12.4%, P = 0.09), the choice of therapy by a clinician rather than the physician performing revascularization (28.9% vs. 11.7%, P = 0.006), and reimbursement availability (31.1% vs. 5.6%, P < 0.0001). Reimbursement availability (OR 6.88; 95% CI 2.60–18.25) and choice of therapy by a clinician (OR 2.69; 95% CI 1.10–6.58) were independent predictors.

Similarly, the prescription of clopidogrel rather than aspirin as SAPT (44.1% of responders) was associated with the choice performed by a clinician rather than by the interventionist/surgeon, both at univariable (57.6% vs. 39.8%; P = 0.07) and multivariable analysis (OR 2.29; 95% CI 1.00–5.27).

The choice of a prolonged duration (≥6 months) of the postprocedural intensified AT (47.5% of responders) was associated with the respondent being a surgeon, both in univariable (57.5% vs. 41.1%, P = 0.055) and at multivariable analysis (OR 2.08; 95% CI 1.10–3.94).

DISCUSSION

Although CLTI exhibits the worst outcomes within the spectrum of atherosclerotic disease and represents an increasing burden worldwide, scientific evidence supporting treatments remain scanty.² Even more, the evidence specifically regarding the type and duration of AT following revascularization is minimal.⁴ In this context of lack of evidence and of lack of standardised assessments of thrombotic and bleeding risks, AT is largely discretional. The present survey provides original insights on the contemporary management of AT in these patients and documents the heterogeneity in the management of CLTI across Europe.

The main findings are:

1. Antithrombotic therapy following surgical revascularization for CLTI varies widely, without a dominant default strategy, and includes the discretional prescription of parenteral or oral anticoagulation for 30% of respondents. Conversely, a default strategy with DAPT following endovascular LER is prescribed according to 80% of respondents, with anticoagulation limited to 6% of cases.

2. An intensified AT is prescribed by 97% of respondents following endovascular LER and by 79% following surgical LER. A longer duration (≥6 months) of the intensified regimen is twice more common among vascular surgeons than among medical specialists and is prescribed more often after surgical vs. endovascular LER, both in standard-bleeding-risk and high-bleeding-risk patients.

3. The prescription of DPI is tightly related to national reimbursement policies, being six-fold higher among respondents from countries with reimbursement.

4. The choice of AT by a clinician in charge of the patient during hospitalization (when different from the physician performing revascularization), is strongly associated with prescription of DPI and of clopidogrel as SAPT.

SAPT, most commonly with aspirin, has remained the mainstay of AT of CLTI for decades. The ‘COhorte de Patients ARTériopathes’ (COPART) registry, a French prospective multicentre registry of hospitalizations for symptomatic LEAD, reported that AT for CLTI consisted of SAPT for most patients and remained unvaried between 2006 and 2016.⁸ In our survey all respondents reported that they prescribe some AT to all CLTI patients undergoing LER, but in contemporary clinical practice there are still patients with an established diagnosis of CLTI who are not receiving any AT. A recent analysis of German health insurance records including 199 953 patients hospitalized for CLTI (63% undergoing LER) reported that in 2018 no AT was prescribed to 27% of patients at 1 year after the index hospitalization.⁹ The use of AT in academic centres is higher; in COPART, among 1981 patients (41% with CLTI), 91% were prescribed AT at discharge.¹⁰ The under-prescription of AT might be related to the perception of a high bleeding risk. Indeed, the above-mentioned German study reported a bleeding rate of 18.8% during hospitalization.⁹ In addition, CLTI is an independent predictor of in-hospital major bleeding in patients undergoing LER (OR 1.61; 95% CI 1.40–1.86),¹¹ and major bleeding is an independent predictor of in-hospital mortality (OR 10.87; 95% CI 6.95–17.02).¹²

Short-term DAPT with aspirin and clopidogrel is the standard of care after endovascular LER and after surgical LER with prosthetic grafts.^1,2 Since CLTI patients are at the highest ischaemic risk within the spectrum of LEAD, it may be argued that an intensified AT with DAPT should be preferred to SAPT in all CLTI patients, even more so following LER. However, no clear-cut evidence supports the routine use of DAPT. The multicentre ‘Clopidogrel and Acetylsalicylic acid in bypass Surgery for Peripheral Arterial disease’ (CASPAR) randomized trial compared DAPT (aspirin plus clopidogrel) with SAPT (aspirin) in patients undergoing surgical infra-popliteal LER (66% CLTI).¹³ No differences in the occurrence of graft occlusion, repeat revascularization, amputation or death were observed between groups (HR 0.98, 95% CI 0.78–1.23), with benefit limited to the subgroup of patients with prosthetic infra-popliteal bypass grafts (HR 0.65, 95% CI 45–0.95). More recently, various registries reported that DAPT vs. SAPT in CLTI patients undergoing LER was associated with fewer MACE and major adverse limb events (MALE), a composite of chronic and acute limb ischaemia, and major amputation due to vascular causes.^14–17 A retrospective analysis of the Vascular Quality Initiative on patients undergoing LER reported that DAPT was associated with a 5-year survival benefit after both surgical (70% vs. 66%; P = 0.04) and endovascular LER (71% vs. 67%; P = 0.01) among CLTI patients, while no benefit was found among claudicants.¹⁵ In a Swedish retrospective analysis on 1941 CLTI patients undergoing endovascular LER, DAPT was associated with a lower rate of amputation only in patients receiving a stent (HR 0.56; 95% CI 0.36–0.86).¹⁶ Given the limitations of observational studies and the lack of dedicated trials on AT for CLTI, useful hints may derive from trials on AT for LEAD in general. A meta-analysis of randomised trials comparing more intense vs. less intense AT (more vs. less intense SAPT; DAPT vs. SAPT; DPI vs. SAPT) found that intensified AT is associated with a significant reduction in the risk of subsequent LER [relative risk (RR) 0.89, 95% CI 0.83–0.94], amputation (RR 0.63, 95% CI 0.46–0.86), and stroke (RR 0.82, 95% CI 0.70–0.97), at the cost of increased risk of major bleeding (RR 1.23, 95% CI 1.04–1.44).¹⁸

The penetration in clinical practice of the concept that a more potent AT therapy might be beneficial in CLTI patients is documented by our survey. In fact, the use an intensified AT (either DAPT or DPI or OAC plus SAPT) was reported by 97% of respondents following endovascular LER and by 79% following surgical LER. Importantly, a prolonged duration (≥6 months) of the postprocedural intensified AT was reported by 50% of respondents for surgical LER and by 36% for endovascular LER in standard-bleeding-risk patients. In high-bleeding-risk patients, a longer duration was preferred by 27 and 18% of respondents for surgical and endovascular LER, respectively. The self-reported wide use of prolonged intensified AT by our respondents might be explained by other two findings of the survey. First, vascular surgeons are twice more likely to prescribe a prolonged duration of intensified AT, possibly because of the perceived risk of graft thrombosis extending beyond 1 month. This perception may also underlie the discretional prescription of parenteral or oral anticoagulants as routine AT following surgical LER by 29% of respondents. Secondly, our respondents probably underestimate the bleeding risk of these patients. In fact, over 40% of respondents estimated the prevalence of high bleeding risk to be <15%. Although the prevalence of high bleeding risk among CLTI patients is unknown, published in-hospital bleeding rates during hospitalization for CLTI are above 15%,⁹ pointing to an even higher prevalence of high bleeding risk.

A major breakthrough for AT in patients undergoing LER recently came from the results of DPI in VOYAGER-PAD⁵ and in the LEAD subgroup of the ‘Cardiovascular Outcomes for People Using Anticoagulation Strategies’ (COMPASS) trial.¹⁹ In particular, DPI is the first AT strategy to demonstrate a significant benefit vs. SAPT on limb events, including acute limb ischaemia (HR 0.67; 95% CI 0.55–0.82) and unplanned LER (HR 0.88; 95% CI 0.79–0.99).⁵ The significant benefit on ischaemic endpoints supports the proposal of DPI as the default strategy following surgical or endovascular LER.⁶ Of note, in VOYAGER-PAD the benefit of DPI on the primary endpoint was uniform across all predefined subgroups, including the 1521 patients (23.2%) suffering from CLTI (HR 0.85; 95% CI 0.69–1.05; P_interaction > 0.2).⁵ In VOYAGER-PAD clopidogrel was administered at physician's discretion to 91% of endovascular patients and 9% of surgical patients. The benefit of DPI on the primary efficacy endpoint was independent of clopidogrel, as well as the primary safety outcome (P_interaction > 0.2 for both endpoints), although clopidogrel duration > 1 month was associated with a higher rate of major bleeding events.²⁰

Both DPI trials reported a significant (but limited) increase in non-fatal bleeding events with DPI in the first year of treatment.^5,19 The safety of DPI has been confirmed by the long-term open-label extension of the COMPASS trial, encompassing 12 964 patients followed-up for an additional median time of 1 year.²¹ The incidence rate for major bleeding was 1.01 (95% CI 0.86–1.19) compared with 1.67 (95% CI 1.48–1.87) during the randomized treatment phase. Consistent results were reported by the prospective ‘Xarelto plus acetylsalicylic acid: treatment patterns and outcomes in patients with atherosclerosis’ (XATOA) registry, enrolling patients who received DPI in clinical practice.²² Among 5532 patients (58.9% with LEAD), major bleeding rates were 0.95 per 100 patient-years, as compared to 1.67 per 100 patient-years in COMPASS.

The applicability of VOYAGER-PAD findings to the real world was retrospectively analysed in COPART.²³ Among 2259 patients evaluated (66% CLTI), only 30.1% resulted eligible for DPI, mainly because of concomitant need for OAC (45%), presence of malignancy (24%), history of stroke (20%), and need for DAPT (16%). Importantly, in the VOYAGER-PAD-eligible subset of COPART, the 1-year MALE rate was 27.9% vs. 6.0% in the control arm of VOYAGER-PAD, indicating a higher ischaemic risk of patients in real-world registries. The applicability of VOYAGER-PAD was also assessed in the Danish Vascular Registry: out of 32 911 patients (47% CLTI), only 27.1% were eligible, with the same distribution of exclusion criteria as for COPART.²⁴ Consistently, the 3-year rate of the VOYAGER-PAD primary efficacy endpoint was higher in the eligible cohort of the registry than in the control arm of the trial (24.1% vs. 19.9%). Notwithstanding the inherent limitations of this type of studies, they consistently indicate that the relevant proportion of real-world patients who would have been eligible for the DPI trials are at higher cardiovascular risk than trial participants, thus suggesting a potentially greater absolute benefit with DPI.

Although the risk/benefit profile of DPI as compared with DAPT with aspirin and clopidogrel is still not fully investigated, the evidence favouring DPI should lead to the routine adoption of this AT following LER for CLTI.⁶ Our survey clearly shows that DPI application is tightly related to the availability of reimbursement and to the choice of AT by clinicians rather than surgeons/interventionists, who are probably focussed more on the technicalities of revascularization than on medical therapy.

Limitations

This survey offers a photograph of prescription patterns by a number of health practitioners dealing with CLTI and willing to reply to a questionnaire solicited by Scientific Societies. Several limitations have to be considered. First, the number of respondents is not very large and we cannot exactly assess the response rate to the survey, as the invitation was sent not only through e-mailing, but also via hyperlinks published on webpages of scientific societies. The estimated response rate is not >50%; therefore, a selection bias of respondents cannot be excluded. The low response rate limits the generalisability of the findings of our survey but is higher than that of most anonymous surveys promoted by scientific societies on a voluntary basis, ranging between 1 and 8%. We believe that the sample size is large enough to be representative, based on the variety of nationality, specialty, and hospital procedural volume. Secondly, we cannot assume that views of the respondents are representative of those of all physicians involved in the management of CLTI patients undergoing revascularization. Thirdly, we did not directly investigate reasons underlying the choice of type and duration of treatment.

Conclusions

With the limitations of self-reported perceptions, the current survey offers an overview of contemporary management of AT in patients undergoing LER for CLTI in Europe. The survey points to the high heterogeneity of treatments, arguing for the need of a better evidence base to guide amid the several alternative therapeutic options in such patients.

Acknowledgment

We thank the ESC Administration Team: Alexandra Henry, Mélissa Kizilian and François Serrano for their help in creating the webpage of the survey.

Funding

None.

Conflict of interest: M.D.C. declares personal consulting fees from Bayer and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, Boehringer Ingelheim, Daiichi Sankyo, Sanofi,

O.S. declares payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Abbott, Bard/BD, Biotronik, Optimed, Bayer.

L.M. declares personal consulting fees from Bayer.

M.B. declares personal consulting fees from Bayer, Biotronik, Boston Scientific, Cook Medical, Medtronic, Philips, Shockwave.

CE. K. declares personal consulting fees from Bayer, Daiichi Sankyo, Pfizer, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Leo Pharma, Sanofi.

D.S. declares personal consulting fees from Bayer, Daiichi Sankyo, Pfizer.

V.A. declares personal consulting fees from Bayer, Pfizer, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, NovoNordisk, Lilly, AstraZeneca.

H.S. declares personal consulting fees from Bayer, Novo Nordisk, Philips.

S.D. declares personal consulting fees from Bayer, Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, AstraZeneca, Sanofi.

M.V. declares personal consulting fees from Bayer.

J.B. declares personal consulting fees from Bayer, Amgen, Rexgenero.

M.F. has nothing to declare.

R.D.C. declares grants from Daiichi Sankyo; Personal consulting fees and payment or honoraria for lectures, presentations, speakers’ bureaus from Bayer, Amgen, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer Alliance, Daiichi Sankyo, AstraZeneca, Guidotti, Menarini, Merck, Novartis, Portola, Roche, Sanofi.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.

References

Author notes