It's not all about ISCHEMIA: the case for coronary artery bypass grafting in stable coronary artery disease.

PURPOSE OF REVIEW: The recent American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions Guidelines for Coronary Artery Revascularization have raised concerns on the survival benefits of coronary artery bypass grafting (CABG) over guideline-directed medical therapy (GDMT) in stable coronary artery disease (CAD) and appropriate conduit selection for CABG. This review summarizes the evidence supporting CABG for stable CAD and use of the radial artery as a conduit for CABG. RECENT FINDINGS: CABG has consistently demonstrated a survival benefit over GDMT for patients with stable multivessel CAD. These benefits were more pronounced in patients with diabetes and/or anatomically complex coronary artery disease. The recently published International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial was not designed to and did not include an appropriate patient population to compare revascularization with CABG to GDMT. These results should thus be viewed in the context of previously published studies. Furthermore, increasing evidence suggests that use of a radial artery in CABG is associated with reduced myocardial infarction and repeat revascularization. This should be considered when selecting the appropriate conduits based on underlying patient factors. SUMMARY: Readers should be cautious when applying these guidelines broadly. Appropriate consideration of patient and anatomic factors, and in consultation with a multidisciplinary heart team, is important to achieve the best outcomes for patients.

Current and future transcatheter aortic valve replacement valves.

PURPOSE OF REVIEW: This review analyzes currently available commercial transcatheter aortic valve replacement (TAVR) valves as well as valves in investigational status and those in preclinical testing. The design features and clinical outcomes of the Edwards SAPIEN S3 and Medtronic Evolut PRO+ are described and compared with highlight clinical circumstances where one may be favoured over the other. RECENT FINDINGS: Multiple randomized and nonrandomized trials have compared commercial and investigational TAVR valves. The results of these are summarized and discussed within this review with a focus on how the SAPIEN S3 and Evolut PRO+ both compare to each other as well as various valves in different investigational stages. SUMMARY: TAVR is an innovative and ground-breaking technology that will forever have revolutionized the management of aortic stenosis. Though the technology and valves themselves have come a long way, further developments are necessary if we are to continue to expand its indications and achieve a safer perioperative experience with more durable valves.

Direct Oral Anticoagulation Versus Warfarin in Patients with Atrial Fibrillation and Bioprosthetic Heart Valves: a Retrospective, Real-World Cohort Study.

OBJECTIVE: In this retrospective cohort study of consecutive patients with atrial fibrillation and surgical or transcatheter bioprosthetic valve, we compared the efficacy and safety of direct oral anticoagulants with warfarin. METHODS: Using linked health administrative databases housed at the Institute for Clinical Evaluative Sciences, we identified consecutive patients in Ontario (Canada) 65 years of age or older with AF who underwent bioprosthetic valve replacement between 1 April 2012 and 31 March 2017. We created a time-varying Cox model to examine the relationship between the type of anticoagulant and time to thrombotic or bleeding events after adjustment for baseline risk of thrombosis using the CHA2DS2-VASc score and risk of bleeding using the HAS-BLED scores. We conducted prespecified subgroup analyses according to whether valve implantation was surgical or transcatheter. RESULTS: We identified 2245 eligible patients. The mean age was 79 years, 41% were female, and 39% had transcatheter aortic valve replacement. Risk of death or thrombosis was not different between direct oral anticoagulants and warfarin after adjustment for CHA2DS2-VASc score (hazard ratio [HR] 1.02, 95% confidence interval [CI], 0.83-1.25). Risk of death or bleeding was not different between direct oral anticoagulants and warfarin after adjustment for HAS-BLED score (HR 0.89, 95% CI 0.75-1.07). Subgroup analyses of surgical or transcatheter valves were consistent with overall results. CONCLUSIONS: In a real-world population of patients with atrial fibrillation and bioprosthetic valve replacement, we found no difference between direct oral anticoagulants and warfarin with regard to the risk of thrombosis or bleeding.

Optimal medical therapy after coronary artery bypass grafting: a primer for surgeons.

PURPOSE OF REVIEW: After coronary artery bypass grafting (CABG), patients remain at increased risk of cardiovascular events and death. Cardiac surgeons have the opportunity to reduce this risk by optimizing post-CABG patients' medical therapy. RECENT FINDINGS: Recent developments in lipid-lowering, diabetes management, antithrombotic therapy, and anti-inflammatory therapy can significantly improve prognosis in patients with chronic coronary artery disease. PCSK-9 inhibitors should be used in patients with elevated LDL cholesterol despite maximally tolerated statin therapy. Icosapent ethyl should be considered in patients with elevated triglycerides despite maximally tolerated statin therapy. Long-acting GLP-1 receptor agonists or SLGT-2 inhibitors should be used in all post-CABG patients with type 2 diabetes. Intensified antithrombotic therapy with DAPT or DPI reduces MACE (and DPI reduces mortality) in patients with high atherosclerotic burden. Colchicine has not yet been incorporated into guidelines on OMT for stable CAD but it is reasonable to consider using it in high-risk patients. SUMMARY: We review the foundations of optimal medical therapy after CABG, and summarize recent advances with a focus on practical application for the busy cardiac surgeon.

Improving outcomes after low-risk coronary artery bypass grafting: understanding phase of care mortality analysis, failure to rescue and recent perioperative recommendations.

PURPOSE OF REVIEW: Avoidable adverse events are responsible for up to 50% of deaths after low-risk coronary artery bypass grafting. This article reviews recent quality improvement efforts to improve outcomes after cardiac surgery. RECENT FINDINGS: Systematic quality improvement methodology in cardiac surgery has improved significantly over the past decade. Contemporary efforts with phase of care mortality analysis (POCMA) focus on identifying and addressing root causes for mortality. Each patient's perioperative course is an interconnected sequence of clinical events, decisions, interventions, and treatment responses occurring across five perioperative phases. A single seminal event within a specific phase of care has been found to often trigger the eventual death of a patient. Several groups have made significant improvements to perioperative outcomes by addressing these avoidable mortality trigger events. Failing that, failure to rescue (FTR) metrics can be used to identify institutional factors responsible for poor perioperative outcomes. This ongoing focus on quality improvement serves to further improve outcomes after low-risk cardiac surgery. SUMMARY: Modern quality improvement methodology, including POCMA and FTR analysis, has the potential to significantly improve outcomes after cardiac surgery. Larger future studies with multiinstitutional data sharing will be key to facilitate ongoing quality improvement and knowledge translation in this field.

Two-year outcomes from the PARTNER 3 trial: where do we stand?

PURPOSE OF REVIEW: The PARTNER 3 trial was conducted to compare outcomes after transcatheter aortic valve replacement (TAVR) with a balloon-expandable valve and surgical aortic valve replacement (SAVR) in individuals at low surgical risk with aortic stenosis. Recently reported rates of death, stoke and valve thrombosis in the TAVR arm have raised concerns about the longevity of this intervention in low-risk individuals. It is incumbent on all members of the Heart Team to understand the potential consequences of these findings. RECENT FINDINGS: TAVR was initially superior to SAVR at 1 year for a primary composite endpoint of death, stroke and rehospitalization. Results at 2 years now indicate noninferiority. Potential causative factors, comparisons with other transcatheter valves and implications for patients, providers and trainees are explored. Recommendations are additionally provided regarding TAVR and SAVR in individuals with aortic stenosis. SUMMARY: Concerns regarding the longevity of TAVR in low-risk individuals notwithstanding, results from PARTNER 3 indicate that TAVR is at least noninferior to SAVR out to 2 years. Longer follow-up will be required to determine whether these newly founded concerns are justifiable.

Ticagrelor use and practice patterns among Canadian cardiac surgeons.

BACKGROUND AND AIM: The P2Y12 platelet receptor inhibitor ticagrelor is widely used in patients following acute coronary syndromes or in those who have received coronary stents. Bentracimab is a monoclonal antibody-based reversal agent that is being formally evaluated in a Phase 3 clinical trial. Here, we probe the knowledge, attitudes, and practice patterns of cardiac surgeons regarding their perioperative management of ticagrelor and potential application of a ticagrelor reversal agent. METHODS: A questionnaire was developed by a working group of cardiac surgeons to inquire into participants' practices and beliefs regarding ticagrelor and disseminated to practicing, Canadian-trained cardiac surgeons. RESULTS: A total of 70 Canadian-trained cardiac surgeons participated. Bleeding risk was identified as the most significant consideration when surgically revascularizing ticagrelor-treated patients (90%). There is variability in the duration of withholding ticagrelor before coronary artery bypass graft procedure in a stable patient; 44.3% wait 3 days and 32.9% wait 4 days or longer. Currently, 15.7% of cardiac surgeons prophylactically give platelet transfusions and fresh frozen plasma intraoperatively following protamine infusion in patients who have recently received ticagrelor. Interestingly, 47.1% of surveyed surgeons were aware of a reversal agent for ticagrelor, 91.4% of cardiac surgeons would consider utilizing a ticagrelor reversal agent if available, and 51.4% acknowledged that the introduction of such an agent would be a major advance in clinical practice. CONCLUSIONS: The present survey identified ticagrelor-related bleeding as a major concern for cardiac surgeons. Surgeons recognized the significant unmet need that a ticagrelor reversal agent would address.

The COMPASS trial: practical considerations for application after coronary artery bypass surgery.

PURPOSE OF REVIEW: We review the cardiovascular outcomes for people using anticoagulation strategies (COMPASS) trial with particular emphasis on patients with a history of remote coronary artery bypass grafting (CABG) and those who were enrolled 4-14 days after CABG. We provide practical guidance for selecting patients with the greatest potential to benefit who have acceptable bleeding risk. In particular, we address concerns about postoperative bleeding and discuss the relative merits of rivaroxaban and aspirin versus P2Y12 inhibition and aspirin. RECENT FINDINGS: The COMPASS trial demonstrated that rivaroxaban and aspirin reduce myocardial infarction, stroke, and cardiovascular death in patients with coronary artery disease, without a demonstrated effect on bypass graft patency in the first postoperative year. SUMMARY: After CABG, cardiac surgeons should consider using the COMPASS regimen in patients at high risk of thrombosis whose risk of bleeding is acceptable. If used, the COMPASS regimen should be continued indefinitely in conjunction with other pharmacological risk reduction therapies to prevent long-term atherothrombotic events.

Knowledge gap of peripheral artery disease starts in medical school.

OBJECTIVE: Previous data suggest that physicians have suboptimal knowledge about peripheral artery disease (PAD). Our aim was to evaluate Canadian medical students' knowledge of PAD to determine if this knowledge gap exists early in medical training. METHODS: We conducted a descriptive, cross-sectional, interview-based study of graduating medical students at the University of Toronto. We used a standardized questionnaire to evaluate students' knowledge of PAD and coronary artery disease (CAD) in the following domains: clinical presentation, risk factors, preventative measures, treatment, and complications. We calculated mean (standard deviation [SD]) scores for each CAD and PAD knowledge domain and examined for differences in PAD vs CAD scores. RESULTS: Seventy-two graduating medical students participated in this study, of which females accounted for 58%. Nearly all participants reported being exposed to PAD (89%) and CAD (92%) through their medical school curriculum. Overall, medical students scored better in identifying CAD characteristics (mean [SD] score, 16.4 [2.7]) compared with PAD (mean [SD] score, 14.6 [3.2]) (P < .0001). This difference was driven by the inferior performance of students in identifying risk factors (P < .0001), preventative measures (P = .049), and complications (P < .0001) of PAD compared with CAD. Out-of-class exposure (eg, clinical rotation, research experience) had a positive impact on students knowledge of both PAD and CAD. CONCLUSIONS: Our results demonstrate suboptimal knowledge of medical graduates of both CAD and PAD. Although they share common atherosclerotic risk factors and cardiovascular complications, medical students were less likely to associate these with PAD than CAD. We recommend a comprehensive module that incorporates all presentations of atherosclerotic disorders to enhance students' understanding of these pathologies in medical schools.

Renin-angiotensin system blockade does not attenuate abdominal aortic aneurysm growth, rupture rate, or perioperative mortality after elective repair.

OBJECTIVE: The objective of this study was to summarize the literature regarding the effects of renin-angiotensin system blockade (RASB) using angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) on human abdominal aortic aneurysm (AAA) growth, rupture, and perioperative mortality. METHODS: We conducted a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Our review protocol was registered at the International Prospective Register of Systematic Reviews (CRD42016054082). We searched the Cochrane Central Register of Controlled Trials database, MEDLINE, and Embase from inception to 2017 for studies examining the effects of ACEi or ARB treatment on AAA growth, rupture, or perioperative mortality. Review, abstraction, and quality assessment were conducted in duplicate, and a third author resolved discrepancies. We assessed study quality using the Cochrane and Newcastle-Ottawa scales. We used random-effects models to calculate pooled mean differences and odds ratios (ORs) with 95% confidence intervals (CIs). Heterogeneity was quantified using the I2 statistic. RESULTS: Our search yielded 525 articles. One randomized and seven observational studies involving 35,448 patients were included. Inter-rater agreement was excellent (κ = 0.78), and risk of bias was low to moderate. All studies investigated ACEis, three studies investigated ARBs, and two studies included a composite RASB group consisting of ACEi or ARB users. Five studies assessed AAA growth, two assessed rupture rate, and one reported 30-day mortality after elective open repair. There was no difference in AAA growth rate between RASB and control (mean difference, 0.03 mm/y; 95% CI, -0.40 to 0.46; P = .88; I2 = 60%). No protective effect of RASB (OR, 0.92; 95% CI, 0.72, 1.16; P = .47; I2 = 90%) was demonstrated for AAA rupture. Finally, RASB increased 30-day mortality in patients undergoing elective open AAA repair (OR, 5; 95% CI, 1.4, 27) according to a single well-adjusted study. CONCLUSIONS: RASB does not appear to affect AAA growth and rupture rate but increases elective perioperative mortality. The small number of heterogeneous, retrospective studies and limited long-term follow-up preclude a definitive dismissal of RASB as pharmacotherapy for AAA. Prospective, long-term data are needed to clarify the effect of RASB on AAA growth, rupture, and perioperative mortality.

Do the Few Dictate Care for the Many? Revascularisation Considerations That Go Beyond the Guidelines.

The burden of coronary artery disease (CAD) is large and growing, commonly presenting with comorbidities and older age. Patients may benefit from coronary revascularisation with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), yet half of patients with CAD who would benefit from revascularisation fall outside the eligibility criteria of trials to date. As such, the choice of revascularisation procedures varies depending on the CAD anatomy and complexity, surgical risk and comorbidities, the patient's preferences and values, and the treating team's expertise. The recent American guidelines on coronary revascularisation are comprehensive in describing recommendations for PCI, CABG, or conservative management in patients with CAD. However, individual challenging patient presentations cannot be fully captured in guidelines. The aim of this narrative review is to summarise common clinical scenarios that are not sufficiently described by contemporary clinical guidelines and trials in order to inform heart team members and trainees about the nuanced considerations and available evidence to manage such cases. We discuss clinical cases that fall beyond the current guidelines and summarise the relevant evidence evaluating coronary revascularisation for these patients. In addition, we highlight gaps in knowledge based on a lack of research (eg, ineligibility of certain patient populations), underrepresentation in research (eg, underenrollment of female and non-White patients), and the surge in newer minimally invasive and hybrid techniques. We argue that ultimately, evidence-based medicine, patient preference, shared decision making, and effective heart team communications are necessary to best manage complex CAD presentations potentially benefitting from revascularisation with CABG or PCI.

How Did We Get Here? Antithrombotic Therapy after Bioprosthetic Aortic Valve Replacement: A Review.

IMPORTANCE: Aortic stenosis is the most common valvular disease, and more than 90% of patients who undergo aortic valve replacement receive a bioprosthetic valve. Yet optimal antithrombotic therapy after bioprosthetic aortic valve replacement remains uncertain, and guidelines provide contradictory recommendations. OBSERVATIONS: Randomized studies of antithrombotic therapy after bioprosthetic aortic valve replacement are small and underpowered. Observational data present opposing, and likely confounded, results. Historically, changes to guidelines have not been informed by high-quality new data. Current guidelines from different professional bodies provide contradictory recommendations despite citing the same evidence. CONCLUSION: Insufficient antithrombotic therapy after bioprosthetic aortic valve replacement has serious implications: ischemic stroke, systemic arterial thromboembolism, and clinical and subclinical valve thromboses. Unnecessarily intense antithrombotic therapy, however, increases risk of bleeding and associated morbidity and mortality. Professional bodies have used the current low-quality evidence and generated incongruent recommendations. Researchers should prioritize generating high-quality, randomized evidence evaluating the risks and benefits of antiplatelet versus anticoagulant therapy after bioprosthetic aortic valve replacement.

Direct oral anticoagulants versus vitamin K antagonists in the first 3 months after bioprosthetic valve replacement: a systematic review and meta-analysis.

OBJECTIVES: We conducted a systematic review and meta-analysis of randomized controlled trials comparing direct oral anticoagulants (DOACs) to vitamin K antagonists (VKAs) in the first 90 days after bioprosthetic valve implantation. METHODS: We systematically searched Embase, Medline and CENTRAL. We screened titles, abstracts and full texts, extracted data and assessed the risk of bias in duplicate. We pooled data using the Mantel-Haenzel method and random effects modelling. We conducted subgroup analyses based on the type of valve (transcatheter versus surgical) and timing of initiation of anticoagulation (<7 vs >7 days after valve implantation). We assessed the certainty of evidence using the Grading of Recommendations, Assessments, Development and Evaluation approach. RESULTS: We included 4 studies of 2284 patients with a median follow-up of 12 months. Two studies examined transcatheter valves (1877/2284 = 83%) and 2 examined surgical valves (407/2284 = 17%). We found no statistically significant differences between DOACs and VKAs with regard to thrombosis, bleeding, death or subclinical valve thrombosis. However, there was a subgroup trend towards more bleeding with DOACs when initiated within 7 days of valve implantation. CONCLUSIONS: In the existing randomized literature on DOACs versus VKAs in the first 90 days after bioprosthetic valve implantation, there appears to be no difference with regard to thrombosis, bleeding or death. Interpretation of the data is limited by small numbers of events and wide confidence intervals. Future studies should focus on surgical valves and should include long-term follow-up to assess any potential impact of randomized therapy on valve durability.

Barriers to Successful Discharge After Cardiac Surgery: A Focus Group Study and Cross-Sectional Survey.

At present, there is a lack of information on patient and caregiver values, and perceived priorities and barriers, to guide successful post-discharge recovery. This was a single center, multiple methods study that investigated patient, caregiver, and health care provider perceptions of the discharge process after cardiac surgery. Themes emerging from focus group discussions with patients and caregivers were used to develop surveys relating to values, barriers, and challenges relating to the discharge process. Thirty-two patients (n = 16) and caregivers (n = 16) participated in four separate focus groups. Four themes emerged from these discussions: (1) a lack of understanding about what the discharge process entails and when discharge is appropriate, (2) issues relating to the information provided to patients at the time of discharge, (3) participant experiences with the health care system, and (4) the experiences of caregivers. Seventy-eight patients, 34 caregivers, 53 nurses and/or other allied health professionals, and 8 surgeons completed the cross-sectional surveys. The most important component of the discharge process for patients and caregivers was "knowing what to do in an emergency." Health care providers less accurately identified what caregivers perceived as the most important aspects of the discharge process.Statements relating to informational barriers to discharge were the most discordant among patient and caregiver respondents. After discharge, patients and caregivers identified the need for longer-term follow up with the surgeon and more support in the community. Incorporation of patient and caregiver values to guide the post-cardiac surgery discharge process is essential to promote successful recovery.

Lessons from the COVID-19 pandemic and recent developments on the communication of clinical trials, publishing practices, and research integrity: in conversation with Dr. David Moher.

BACKGROUND: The torrent of research during the coronavirus (COVID-19) pandemic has exposed the persistent challenges with reporting trials, open science practices, and scholarship in academia. These real-world examples provide unique learning opportunities for research methodologists and clinical epidemiologists-in-training. Dr. David Moher, a recognized expert on the science of research reporting and one of the founders of the Consolidated Standards of Reporting Trials (CONSORT) statement, was a guest speaker for the 2021 Hooker Distinguished Visiting Professor Lecture series at McMaster University and shared his insights about these issues. MAIN TEXT: This paper covers a discussion on the influence of reporting guidelines on trials and issues with the use of CONSORT as a measure of quality. Dr. Moher also addresses how the overwhelming body of COVID-19 research reflects the "publish or perish" paradigm in academia and why improvement in the reporting of trials requires policy initiatives from research institutions and funding agencies. We also discuss the rise of publication bias and other questionable reporting practices. To combat this, Dr. Moher believes open science and training initiatives led by institutions can foster research integrity, including the trustworthiness of researchers, institutions, and journals, as well as counter threats posed by predatory journals. He highlights how metrics like journal impact factor and quantity of publications also harm research integrity. Dr. Moher also discussed the importance of meta-science, the study of how research is carried out, which can help to evaluate audit and feedback systems and their effect on open science practices. CONCLUSION: Dr. Moher advocates for policy to further improve the reporting of trials and health research. The COVID-19 pandemic has exposed how a lack of open science practices and flawed systems incentivizing researchers to publish can harm research integrity. There is a need for a culture shift in assessing careers and "productivity" in academia, and this requires collaborative top-down and bottom-up approaches.

Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Postoperative atrial fibrillation (POAF) after cardiac surgery is associated with longer hospital stay and increased in-hospital death and stroke, but its long-term implications remain incompletely understood. A systematic literature review was undertaken to investigate the impact of POAF on long-term death and stroke in adult patients who undergo cardiac operations. METHODS: Electronic databases (Cochrane, Embase, Ovid MEDLINE, and PubMed) were queried from inception to October 2018. Included studies compared long-term outcomes after cardiac operations in patients with and without POAF. Adjusted and unadjusted meta-analyses examined death, stroke, and major adverse cardiac and cerebrovascular events. Risk of bias was evaluated with the Newcastle-Ottawa Scale. RESULTS: The inclusion criteria were met by 32 studies describing 155,575 patients who had undergone cardiac operations. POAF occurred in 36,988 patients (23.7%). Meta-analysis of 10 studies (44,367 patients) demonstrated increased 1-year death in patients with POAF (odds ratio, 2.60; 95% confidence interval, 2-3.38; P < .01). Aggregate adjusted hazard of death (16 studies, n = 84,295) was also increased in patients with POAF (hazard ratio, 1.25; 95% confidence interval, 1.2-1.3; P < .01). CONCLUSIONS: This systematic review and meta-analysis identified an association between POAF and long-term death after cardiac surgery. More comprehensive POAF prevention and management, including more stringent follow-up for POAF recurrence after hospital discharge, may be indicated. The included studies used inconsistent definitions of POAF and variable exclusion criteria; however, estimates of heterogeneity are low. Differences in preoperative comorbidities, such as age, ejection fraction, and obesity, may not be fully accounted for in adjusted analyses. Future work is required to delineate mechanisms linking POAF and death in this population.

Infective Endocarditis Secondary to Injection Drug Use: A Survey of Canadian Cardiac Surgeons.

BACKGROUND: Injection drug use-associated infective endocarditis (IDU-IE) is a growing epidemic. The objective of this survey was to identify the beliefs and practice patterns of Canadian cardiac surgeons regarding surgical management of IDU-IE. METHODS: A 30-question survey was developed by a working group and distributed to all practicing adult cardiac surgeons in Canada. Data were analyzed using descriptive statistics. RESULTS: Of 146 surgeons, 94 completed the survey (64%). Half of surgeons (49%) would be less likely to operate on patients with IE if associated with IDU. In the case of prosthetic valve IE owing to continued IDU, 36% were willing to reoperate once and 14% were willing to reoperate twice or more. Most surgeons required commitments from patients before surgery (73%), and most referred patients to addiction services (81%). Some surgeons would offer a Ross procedure (10%) or homograft (8%) for aortic valve IE, and 47% would consider temporary mechanical circulatory support. Whereas only 17% of surgeons worked at an institution with an endocarditis team, 71% agreed that there was a need for one at each institution. Most surgeons supported the development of IDU-IE-specific guidelines (80%). CONCLUSIONS: Practice patterns and surgical management of IDU-IE vary considerably across Canada. Areas of clinical unmet needs include the development of a formal addiction services referral protocol for patients, the development of an interdisciplinary endocarditis team, as well as the creation of IDU-IE clinical practice guidelines.