TYPE Original Research PUBLISHED 26 July 2022 DOI 10.3389/fcvm.2022.916031 An intensive, structured, mobile OPEN ACCESS devices-based healthcare EDITED BY Nathalie Pamir, Oregon Health and Science University, intervention to optimize the United States REVIEWED BY lipid-lowering therapy improves Federico Vancheri, S. Elia Hospital, Italy Krzysztof Dyrbus, 0 lipid control after an acute Silesian Center for Heart Diseases, Poland Oliver Weingärter, coronary syndrome University Hospital Jena, Germany *CORRESPONDENCE Sonia Ruiz-Bustillo1,2,3,4*, Neus Badosa1,2 , Sonia Ruiz-Bustillo sruiz@psmar.cat Ignacio Cabrera-Aguilera1,5,6 , Consol Ivern1,2 , SPECIALTY SECTION Marc Llagostera2 , Diana Mojón2 , Miren Vicente2 , This article was submitted to Núria Ribas1,2 , Lluis Recasens1,2 , Julio Martí-Almor1,2,3 , Lipids in Cardiovascular Disease, a section of the journal Mercè Cladellas1,2,3 and Núria Farré1,2,3,4 Frontiers in Cardiovascular Medicine 1 Heart Diseases Biomedical Research Group, IMIM (Hospital del Mar Medical Research Institute), RECEIVED 08 April 2022 Barcelona, Spain, 2 Cardiac Rehabilitation Unit, Department of Cardiology, Hospital del Mar, ACCEPTED 08 July 2022 Barcelona, Spain, 3 Departament of Medicine, Autonomous University of Barcelona, Barcelona, PUBLISHED 26 July 2022 Spain, 4 Department of Medicine, Pompeu Fabra University, Barcelona, Spain, 5 Unitat de Biofísica i Bioenginyeria, Facultat de Medicina i Ciéncies de la Salut, Universitat de Barcelona, Barcelona, CITATION Spain, 6 Department of Human Movement Sciences, Faculty of Health Sciences, School of Ruiz-Bustillo S, Badosa N, Kinesiology, Universidad de Talca, Talca, Chile Cabrera-Aguilera I, Ivern C, Llagostera M, Mojón D, Vicente M, Ribas N, Recasens L, Martí-Almor J, Cladellas M and Farré N (2022) An intensive, structured, mobile devices-based healthcare intervention Aims: Despite the evidence, lipid-lowering treatment (LLT) in secondary to optimize the lipid-lowering therapy prevention remains insufficient, and a low percentage of patients achieve the improves lipid control after an acute coronary syndrome. recommended LDL cholesterol (LDLc) levels by the guidelines. We aimed to Front. Cardiovasc. Med. 9:916031. evaluate the efficacy of an intensive, mobile devices-based healthcare lipid- doi: 10.3389/fcvm.2022.916031 lowering intervention after hospital discharge in patients hospitalized for acute COPYRIGHT coronary syndrome (ACS). © 2022 Ruiz-Bustillo, Badosa, Cabrera-Aguilera, Ivern, Llagostera, Methods and results: Ambiespective register in which a mobile devices-based Mojón, Vicente, Ribas, Recasens, Martí-Almor, Cladellas and Farré. This healthcare intervention including periodic follow-up, serial lipid level controls, is an open-access article distributed and optimization of lipid-lowering therapy, if appropriate, was assessed in under the terms of the Creative Commons Attribution License (CC BY). terms of serum lipid-level control at 12 weeks after discharge. A total of The use, distribution or reproduction in 497 patients, of which 462 (93%) correctly adhered to the optimization other forums is permitted, provided protocol, were included in the analysis. At the end of the optimization period, the original author(s) and the copyright owner(s) are credited and that the 327 (70.7%) patients had LDLc levels ≤ 70 mg/dL. 40% of patients in the original publication in this journal is LDLc ≤ 70 mg/dL group were upgraded to very-high intensity lipid-lowering cited, in accordance with accepted academic practice. No use, distribution ability therapy vs. 60.7% in the LDLc > 70 mg/dL group, p < 0.001. Overall, or reproduction is permitted which 38.5% of patients had at least a change in their LLT. Side effects were relatively does not comply with these terms. infrequent (10.7%). At 1-year follow-up, LDLc levels were measured by the primary care physician in 342 (68.8%) of the whole cohort of 497 patients. In this group, 71.1% of patients had LDLc levels ≤ 70 mg/dL. Frontiers in Cardiovascular Medicine 01 frontiersin.org Ruiz-Bustillo et al. 10.3389/fcvm.2022.916031 Conclusion: An intensive, structured, mobile devices-based healthcare intervention after an ACS is associated with more than 70% of patients reaching the LDLc levels recommended by the clinical guidelines. In patients with LDLc measured at 1-year follow-up, 71.1% had LDLc levels ≤ 70 mg/dL. KEYWORDS ischemic heart disease, secondary prevention, cardiovascular risk factors, lipid- lowering therapy, mobile devices-based healthcare Introduction the efficacy and safety of a lipid-lowering intervention to improve the management of LDLc levels in patients hospitalized There is extensive evidence confirming the benefit of cardiac for IHD (ClinicalTrials.gov Identifier: NCT03619395). Between rehabilitation programs (CRP) in patients with ischemic heart July 2018 and September 2019, all patients hospitalized for IHD disease (IHD) (1). An intensive CRP reduces cardiovascular risk in our hospital not meeting any exclusion criteria (inability or through lifestyle changes (2). However, correct pharmacological refusal to sign the informed consent or presenting comorbidities treatment is also crucial for optimal cardiovascular risk with a life expectancy of less than 1 year) and willing to factors control, including dyslipidemia. The drop in low- participate in the CRP were screened for inclusion in this density lipoprotein cholesterol (LDLc) levels in secondary study. All patients providing written informed consent were prevention significantly reduces mortality, coronary events, included in the RiskOp-ACS register. The Ethics Committee of coronary revascularization procedures, and ischemic strokes (3). the Hospital del Mar approved the study and was conducted per Despite the evidence, lipid-lowering treatment (LLT) in the Declaration of Helsinki. The Ethics Committee approved secondary prevention remains insufficient, and a low percentage the retrospective inclusion of patients who followed the same of patients achieve the LDLc levels recommended by the protocol since November 2016 to increase the sample size guidelines (4–6). One factor explaining this contradiction is and waived the need for written informed consent. Therefore, the so-called therapeutic inertia, defined as the failure of all patients included in the study (both prospectively and physicians to initiate or intensify an indicated therapy (7). Other retrospectively) followed the same optimization protocol. significant barriers are lack of infrastructure and availability of CRP, lack of perceived importance of secondary prevention among professionals, and low patient motivation and financial difficulties to pay the LLT (8). Cardiac rehabilitation program Mobile devices-based healthcare (mHealth) aimed at improving patients’ living standards (9) can be an effective tool The multidisciplinary CRP performed in our center is to improve the suboptimal results in dyslipidemia control (10). coordinated by specialized nurses. It includes interventions Considering the disappointing results in secondary prevention, performed by cardiologists, nurses, rehabilitation physicians, we conducted a randomized pilot study to evaluate whether and professionals specialized in managing anxiety and other an intensive mHealth lipid-lowering intervention implemented mental health disorders. All patients discharged after a after a hospitalization due to IHD was associated with a lower hospitalization for an acute IHD event and with no severe LDLc level. We demonstrated that this strategy was associated cognitive impairment are invited to the CRP. As part of the with improved management of LDLc levels compared with program activities, nurses educate patients in healthy habits standard care alone (11). Our current study aimed to assess during the in-hospital stage and at follow-up visits at 3 and whether this same structured mHealth-based protocol helped 12 months after discharge; provide and monitor the quality of improve LDLc levels after a hospitalization due to IHD in a life, anxiety, and depression symptoms using validated tests, real-life population. and coordinate the follow-up plan and visits. Rehabilitation physicians and physiotherapists assess the patient’s functional status and indicate and supervise physical activity during follow- Materials and methods up. All professionals involved in the CRP participate in monthly group sessions aimed at reinforcing the health education of Study design and participants the patients, with a particular focus on increasing the patients’ understanding of the pathophysiology of IHD, on the role The Risk Optimization Acute Coronary Syndrome (RiskOp- of cardiovascular risk factors, and the importance of optimal ACS) study was a single-center ambispective register assessing risk factor management, mainly through physical activity, Frontiers in Cardiovascular Medicine 02 frontiersin.org Ruiz-Bustillo et al. 10.3389/fcvm.2022.916031 control of anxiety, and adherence to guideline-recommended among others. As an exploratory analysis, the number of pharmacotherapies. patients who reached LDLc levels < 55 mg/dL at the end of the optimization period was also analyzed. Finally, we assessed also as an exploratory analysis, clinical outcomes Intervention with the achievement of LDL ≤ 70 mg/dL at the end of the optimization period. All patients were discharged under LLT. Serum lipid levels were measured at week 6 after discharge, and a virtual visit with the cardiologist was made within 1 week of the Statistical analyses blood test. The laboratory test results were evaluated using a pre-specified algorithm based on clinical practice guidelines Data for continuous variables are expressed as (Supplementary Figure 1). If there was a need to modify mean ± standard deviation (SD) or median and interquartile the LLT, the electronic prescription was changed accordingly, range (IQR) based on normality distribution assessed by and the patient was informed by phone. Thus, the protocol Kolmogorov-Smirnov test. Categorical variables were expressed avoided the need to come to the hospital or primary care center as percentages. Differences in baseline characteristics between since the medication could be retrieved directly from the local groups were tested using the χ2 -test (categorical variables) and pharmacy or printed/seen in the personal health record through Student’s t-test or Mann–Whitney U-test, one-way analysis of a dedicated app/website created by the Health Department variance, or Kruskal-Wallis test for continuous variables. All (Lamevasalut). This intervention was repeated every 6 weeks analysis was performed using IBM SPSS Statistics v25 (Armonk, after every pharmacological change until the target LDLc levels NY, United States). For all tests, p < 0.05 was considered as (calculated by the Friedewald formula) advised in the clinical statically significant. guidelines were achieved, or maximum lipid-lowering therapy according to local regulation was reached. Thus, the duration of the intervention was a maximum of 3 months (“optimization Results period”). From that moment, the follow-up was performed by the patient’s primary care general physician and primary care The whole cohort included 497 patients, of which 462 cardiologist. Creatinine kinase and liver tests were measured in (93%) correctly adhered to the optimization protocol and were all blood tests following LLT modification. included in the analysis. At the end of the optimization period, The LLT intensity was defined according to its ability to 327 (70.7%) patients had LDLc levels ≤ 70 mg/dL, and 159 reduce LDLc (12, 13). The moderate lipid-lowering ability group (34.7%) had LDLc levels < 55 mg/dL. comprises moderate-intensity statins and low-intensity statin According to LDLc levels achieved, baseline characteristics plus ezetimibe. High-intensity statins, and medium-intensity of patients are described in Table 1. Interestingly, the only statins plus ezetimibe are the high-reduction group. High- differences between both groups were a higher prevalence of potency statins plus ezetimibe are the very-high reduction chronic obstructive pulmonary disease in the LDLc ≤ 70 mg/dL group. Finally, PCSK9 inhibitor added at maximally tolerated group and different history of smoking. doses to LLT is considered extreme reduction ability treatment Table 2 shows LDLc levels at baseline and during follow- (Supplementary Table 1). In our country, the prescription of up, the type of LLT given, and the presence of side effects. PCSK9 inhibitors is allowed in the public health system for Interestingly, LLT did not differ at discharge from the hospital, patients with established cardiovascular disease and no optimal with 65% of patients on high lipid-lowering ability treatment. control defined as LDLc > 100 mg/dL despite the maximum However, by the end of the optimization therapy, 40% of tolerated dose of statins, patients intolerant to statins, or in patients in the LDL ≤ 70 mg/dL levels were upgraded to whom statins are contraindicated (14). very-high intensity lipid-lowering ability vs. 60.7% in the LDL levels > 70 mg/dL, p < 0.001. Overall, 38.5% of patients had at least a change in their LLT. The LDLc levels > 70 mg/dL Study endpoints group had a higher number of changes in medications (61.4 vs. 27.5%, p < 0.001). However, this treatment modification was The primary study endpoint was the proportion of patients not enough to achieve good LDLc control in this group. During with serum LDLc levels ≤ 70 mg/dL at the end of the the optimization period, only 14 (2.8%) received extreme lipid- optimization period, which was the treatment goal supported lowering ability treatment with PCSK-9 inhibitors, 5 (1.5%) by current ESC guidelines (15) when the study was conducted. patients in the LDLc ≤ 70 mg/dL, and 9 (6.9%) patients in the Other variables related to lipid management assessed during the LDL levels > 70 mg/dL, p = 0.003. intervention included lipid-lowering medication use, changes Side effects were relatively infrequent, with 53 reports in lipid-lowering medication, and the presence of side effects, (10.7%) of the cohort (patients could have more than one side Frontiers in Cardiovascular Medicine 03 frontiersin.org Ruiz-Bustillo et al. 10.3389/fcvm.2022.916031 TABLE 1 Baseline characteristics of patients according to LDLc levels after the optimization protocol. LDLc ≤ 70 mg/dL (n = 327) LDLc > 70 mg/dL (n = 135) P-value Age (years) 62.9 ± 11.6 62.9 ± 11.9 0.98 Women (n, %) 56 (17.1) 30 (22.9) 0.15 BMI (Kg/m2) 27.7 ± 4.0 27.7 ± 4.6 0.95 Risk factors and comorbidities Hypertension (n, %) 185 (56.6) 72 (55) 0.75 Hyperlipidemia (n, %) 207 (63.3) 94 (71.8) 0.09 Diabetes mellitus (n, %) 100 (30.6) 33 (25.2) 0.25 Current smoker (n, %) 119 (36.4) 65 (49.6) 0.008 Previous smoker > 1 year (n, %) 114 (34.9) 29 (22.1) Previous smoker < 1 year (n, %) 16 (4.9) 2 (1.5) Previous ACS-MI (n, %) 60 (18.3) 25 (19.1) 0.86 COPD (n, %) 32 (9.8) 5 (3.8) 0.02 Cerebrovascular disease (n, %) 18 (5.5) 5 (3.8) 0.46 Peripheral vascular disease (n, %) 25 (7.6) 9 (6.9) 0.78 Anemia (n, %) 53 (16.2) 28 (21.4) 0.19 Chronic kidney disease (n, %) 21 (6.4) 7 (5.3) 0.66 Index hospitalization STEMI (n, %) 140 (42.8) 60 (45.8) 0.79 NSTEMI (n, %) 118 (36.1) 43 (32.8) Unstable Angina (n, %) 69 (21.1) 28 (21.4) One vessel disease (n, %) 170 (52) 76 (58) 0.29 Two vessel disease (n, %) 85 (26) 28 (21.4) Three vessel disease (n, %) 63 (19.3) 20 (15.3) Left main disease (n, %) 14 (4.3) 9 (6.9) 0.25 Coronary percutaneous angioplasty (n, %) 280 (85.6) 107 (81.7) 0.29 Ejection fraction (%) 56.4 ± 10.0 55.6 ± 10.2 0.42 Data are mean ± SD, median (IQR), or n (%). BMI, Body mass index; COPD, chronic obstructive pulmonary disease; CV, Cardiovascular; STEMI, ST-elevation myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; ACS-MI, Acute coronary syndrome-myocardial infarction. effect reported). The more common side effects were abnormal vs. 22 (16.4%), p = 0.054] compared to those who did not achieve asymptomatic liver tests, increased creatine-kinase levels, and an LDLc ≤ 70 mg/dL. myalgia. However, these side effects were rarely associated with LLT discontinuation. In most cases, side effects led to a change or temporary suspension in LLT in 4.3% of patients, without Discussion differences in both groups. At 1-year follow-up, LDLc levels were measured by the local Our study showed that an intensive, structured, mHealth cardiologist or primary care physician in 342 (68.8%) of the post-discharge follow-up plan to optimize the lipid-lowering whole cohort of 497 patients. In this group, 71.1% of patients pharmacotherapy was associated with achieving a target had LDLc levels ≤ 70 mg/dL. Interestingly, 77.4% of patients LDLc ≤ 70 mg/dL in 70.7% of patients after an acute coronary with LDL ≤ 70 mg/dL at the end of optimization still had LDL syndrome (ACS). Reduction and achievement of LDLc target levels ≤ 70 mg/dL at 1-year follow-up, whereas 59.6% of patients value were obtained early (between 6 and 12 weeks after who did not reach LDLc ≤ 70 mg/dL did so at 1 year. the ACS) as recommended in the literature (16). It is also At a median follow-up of 30 (p25–75: 21–38) months, important to emphasize that the intervention was carried out patients who achieved an LDLc ≤ 70 mg/dL after the using low-cost phone-based telemedicine techniques (mHealth) optimization protocol had a numerically lower incidence of that facilitate its implementation and patient follow-up. The use myocardial infarction [12 (3.6%) patients vs. 10 (7.5%), p = 0.08], of mHealth might explain why less than 8% of the patients did need of new revascularization [22 (6.7%) patients vs. 10 (7.5%), not adhere to follow-up. p = 0.77), death (12 (3.6%) patients vs. 8 (6%), p = 0.27], and the Considering the few significant baseline characteristics composite end-point that comprised the 3 outcomes [33 (10%) differences between the LDLc ≤ 70 mg/dL and Frontiers in Cardiovascular Medicine 04 frontiersin.org Ruiz-Bustillo et al. 10.3389/fcvm.2022.916031 TABLE 2 Baseline LDL levels and medication changes according to LDL levels reached. LDLc ≤ 70 mg/dL (n = 327) LDLc > 70 mg/dL (n = 135) P-value Baseline LDLc 103.9 ± 36.6 115.2 ± 45.2 0.012 End of optimization LDLc 53.4 ± 10.1 85.0 ± 16.7 < 0.001 1 LDLc at the end of optimization (absolute reduction) −50.0 (−21, −77) −31.0 (+ 2, −53) < 0.001 1 LDLc at the end of optimization (relative reduction) −47.5 (−25, −60.1) −26.2 (+ 2.6, −41.0) < 0.001 1-year LDLc levels 61.5 ± 18.3 69.9 ± 25.4 0.003 Baseline LLT Moderate lowering ability (n, %) 17 (5.3) 7 (5.4) 0.21 High lowering ability (n, %) 206 (63.8) 88 (68.2) Very high lowering ability (n, %) 96 (29.7) 30 (23.3) LLT end of optimization Moderate lowering ability (n, %) 15 (4.5) 3 (2.2) < 0.001 High lowering ability (n, %) 171 (52.2) 40 (29.6) Very high lowering ability (n, %) 131 (40) 82 (60,7) Extreme lowering ability (n, %) 5 (1.5) 10 (7.4) Number of side effects reported (n, %) 38 (11.8) 15 (11.6) 0.97 Side effects Liver test abnormalities (n, %) 24 (7.3) 6 (4.4) 0.30 Creatine Kinase increase (n, %) 6 (1.8) 4 (2.9) Myalgia (n, %) 3 (0.9) 4 (2.9) Change in LLT (n, %) 90 (27.5) 83 (61.4) < 0.001 LLT at 1 year Moderate lowering ability (n, %) 11 (4.5) 2 (2) 0.46 High lowering ability (n, %) 113 (46.1) 45 (45) Very high lowering ability (n, %) 117 (47.8) 51 (51) Data are mean ± SD, median (IQR), or n (%). LDLc, low-density lipoprotein cholesterol LLT; lipid lowering therapy. LDLc > 70 mg/dL groups, these differences did not allow for high and very high-risk patients. The recommendations us to identify those patients who would achieve proper regarding the treatment goals for LDLc are based in the studies LDLc control. It is worth mentioning that the percentage of that have shown that the lower the LDLc level the better (17). patients achieving LDLc ≤ 70 mg/dL in this real-life study These guidelines were not published during the performance is even better than the results we obtained in a previous of our study. In our cohort, 34.7% of the patients achieved randomized study in which we used the same strategy, where an LDLc < 55 mg/dL. It is worth noting that it was not an LDLc ≤ 70 mg/dL was achieved in 62% of the patients the target level of our study and, thus, there was some room (10). Moreover, these results contrast positively with the poor for LLT optimization. This result improves that reported in results described in our hospital before implementing the the DA VINCI study; being one of the first comparative study intervention (4). This insufficient control of dyslipidemia analyses evaluating 2019 risk-based goal attainment, showed in very high-risk patients coincides with that described that three-quarters of patients did not meet their 2019 LDLc more recently in the literature. The ESC-EORP Euroaspire goals (18). V survey performed in 27 European countries showed that The inability to achieve an LDLc level ≤ 70 mg/dl was the prevalence of LDLc ≤ 70 mg/dL in the entire cohort not due to therapeutic inertia. Intensifications or treatment was 30% (5). Similar findings were found in a retrospective changes were done in 64% of the patients. When changes analysis of patients with ACS in Finland, where two-thirds were not made, patients were already on the maximum dose of patients on statin therapy did not achieve the LDLc of oral treatment, did not tolerate a higher dose or did level target recommended by the guidelines (6). According not meet the local criteria for using PCSK9 inhibitors. This to these data, our strategy could more than double the intensification effort is superior to the ones described in number of patients with adequate LDLc level control after a the literature. The GOULD prospective observational registry hospitalization due to IHD. study was carried out simultaneously in the United States. The most recent ESC/EAS guidelines for the management A total of 5,006 patients with established atherosclerotic of dyslipidemias published in 2019 advise an LDLc < 55 mg/dL cardiovascular disease were enrolled. Surprisingly, only 17% Frontiers in Cardiovascular Medicine 05 frontiersin.org Ruiz-Bustillo et al. 10.3389/fcvm.2022.916031 had LLT intensification after 2 years, while two-thirds remained After the treatment optimization period, the patient’s at an LDLc level > 70 mg/dL (19). Another important primary care general physician and primary care cardiologist finding in our study is that 95% of the patients at the performed the follow-up. We decided to analyze whether the end of the optimization period were treated with drugs good results achieved in the first 3 months were maintained included in the high, very high, or extreme lipid-lowering after 12 months. Surprisingly, 31% of the patients did not have a ability groups. In the register published by Navar et al., of follow-up blood test at month 12. In those patients who did have almost 3,297 patients analyzed, only 47% of the patients an LDLc assessment at 1 year, 71.1% of the patients maintained who required secondary prevention were treated with the an LDLc ≤ 70 mg/dl. This group comprises 77.4% of the patients appropriate intensity of treatment (20). One of the hypotheses who already had an LDLc ≤ 70 mg/dl initially and patients that may justify not achieving an optimal decrease in LDLc, who had not reached this target level originally (59.6%). This despite treatment is the described lack of response to statin percentage of patients with a target LDLc level after 12 months treatment. A meta-analysis of genome-wide association studies remains significantly higher than the results reported in the showed that two loci of the genome are responsible for about literature (4–6). 5% of the variation in an individual’s response to statin Our study used the simplest and most readily usable form treatment (21). The JUPITER study highlights that 43% of of mHealth, such as telephone calls. We believe that it was a high-risk patients had an LDLc reduction < 50 and 11% determining factor in the success of this follow-up protocol. showed no reduction or even an increase in LDLc with statin A randomized study in Sweden (29) and a meta-analysis treatment (22). of randomized controlled trials (10) showed improved LDLc Large cardiovascular outcomes trials showed a prognostic levels with mHealth. benefit with PCSK9 inhibitors monoclonal antibodies (23, 24), and it has been estimated that 30% of patients could Limitations be candidates of PCSK9 inhibitors (25). However, the use of PCSK9 inhibitors in our study was low due to As a single-center study, the results might not apply to other prescription restrictions in our country. PCSK9 inhibition settings. Some of the patients were included retrospectively, obtains further lowering of LDLc beyond that achieved potentially leading to bias. Still, given that all patients followed with statin therapy and cholesterol absorption inhibitors; an the same protocol and that the information was documented incremental reduction in LDLc of 50% from baseline has in the medical record, we believe that the risk of bias in this been shown (26). Knowing that the LDLc levels in the group study is negligible. with LDLc > 70 mg/dL were 85.0 ± 16.7 mg/dL and the hypothetical additional reduction of 50%, we theorized that we could have even achieved 100% of patients with LDLc Conclusion target levels if we had been allowed to expand the use of PCSK9 inhibitors. An intensive, structured, mobile devices-based healthcare Numerous studies with lipid-lowering drugs have intervention after an ACS is associated with more than 70% shown that the reduction of LDLc levels translates into a of patients reaching the LDLc levels recommended by the reduction in cardiovascular events, giving rise to the current clinical guidelines. This strategy uses low-cost and easy-to- recommendations in secondary prevention (17). We saw apply telemedicine techniques that can be replicated in various that patients who achieved an LDLc ≤ 70 mg/dL after the clinical settings. optimization protocol had numerically fewer clinical endpoints. However, it is important to remark that the study was underpowered to detect hard endpoint due to the relatively Data availability statement small sample size and the number of events. One of the reasons that might limit LLT is side effects. Some The original contributions presented in this study are included in the article/Supplementary material, further physicians and patients might be reluctant to begin or maintain inquiries can be directed to the corresponding author. statins, most commonly because of perceived side effects that are not confirmed (i.e., the nocebo effect) (27). However, statins are generally well-tolerated drugs (25). 11% of the patients had any Ethics statement side effects in our cohort, with no significant differences between the LDLc group ≤ 70 mg/dL and the LDLc group > 70 mg/dL. The patients/participants prospectively included in The most frequent side effect was the liver tests abnormalities the study provided their written informed consent. The (79%), followed by an increase in creatinine kinase (26%) and patients/participants included retrospectively did not require finally myalgias (18%). These data are comparable to those informed consent after evaluation by the Research Ethics previously described (15, 28). Committee of the Hospital del Mar. Frontiers in Cardiovascular Medicine 06 frontiersin.org Ruiz-Bustillo et al. 10.3389/fcvm.2022.916031 Author contributions Publisher’s note SR-B: conceptualization and writing original draft All claims expressed in this article are solely those of the preparation. SR-B and NF: methodology, project authors and do not necessarily represent those of their affiliated administration, and validation. NF: formal analysis and organizations, or those of the publisher, the editors and the writing – review and editing. SR-B, NB, CI, NF, and NR: reviewers. Any product that may be evaluated in this article, or investigation. IC-A, MV, DM, ML, LR, SR-B, and NF: data claim that may be made by its manufacturer, is not guaranteed curation. NB, CI, IC-A, DM, MV, ML, NR, LR, JM-A, and or endorsed by the publisher. MC: visualization. NF, JM-A, and MC: supervision. All authors contributed to the article and approved the submitted version. Supplementary material The Supplementary Material for this article can be Conflict of interest found online at: https://www.frontiersin.org/articles/10.3389/ fcvm.2022.916031/full#supplementary-material The authors declare that the research was conducted in the absence of any commercial or financial relationships that could SUPPLEMENTARY FIGURE 1 be construed as a potential conflict of interest. Lipid-lowering treatment optimization algorithm. References 1. Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Bäck M, et al. 11. Ruiz-Bustillo S, Ivern C, Badosa N, Farre N, Marco E, Bruguera J, et al. 2021 ESC guidelines on cardiovascular disease prevention in clinical practice. Eur Efficacy of a nurse-led lipid-lowering secondary prevention intervention in patients Heart J. (2021) 42:3227–337. doi: 10.1093/eurheartj/ehab484 hospitalized for ischemic heart disease: a pilot randomized controlled trial. Eur J Cardiovasc Nurs. (2019) 18:366–74. doi: 10.1177/1474515119831511 2. Wood DA, Kotseva K, Connolly S, Jennings C, Mead A, Euroaction Study Group, et al. Nurse-coordinated multidisciplinary, family-based cardiovascular 12. Masana L, Pedro-Botet J, Civeira F. IMPROVE-IT clinical implications. disease prevention programme (EUROACTION) for patients with coronary heart Should the “high-intensity cholesterol-lowering therapy” strategy replace the disease and asymptomatic individuals at high risk of cardiovascular disease: a “high-intensity statin therapy”? Atherosclerosis. (2015) 240:161–2. doi: 10.1016/j. paired, cluster-randomised controlled trial. Lancet. (2008) 371:1999–2012. doi: 10. atherosclerosis.2015.03.002 1016/S0140-6736(08)60868-5 13. Escobar C, Anguita M, Arrarte V, Barrios V, Cequier A, Cosín-Sales J, et al. 3. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder Recommendations to improve lipid control. Consensus document of the Spanish R, et al. Intensive versus moderate lipid lowering with statins after acute society of cardiology. Rev Esp Cardiol. (2020) 73:161–7. doi: 10.1016/j.rec.2019.08. coronary syndromes. N Engl J Med. (2004) 350:1495–504. doi: 10.1056/NEJMoa04 012 0583 14. Agencia Española de Medicamentos y Productos Sanitarios. Informe de 4. Ribas N, García-García C, Meroño O, Recasens L, Pérez-Fernández S, Bazán Posicionamiento Terapéutico de Evolocumab en Hipercolesterolemia. Fecha de V, et al. Secondary prevention strategies after an acute ST-segment elevation Adopción de la Actualización de la Fase I del Informe Por el GCPT. Madrid: Agencia myocardial infarction in the AMI code era: beyond myocardial mechanical Española de Medicamentos y Productos Sanitarios (2020). reperfusion. BMC Cardiovasc Disord. (2017) 17:54. doi: 10.1186/s12872-017- 15. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, 0493-6 et al. ESC scientific document group. 2016 European guidelines on cardiovascular 5. De Backer G, Jankowski P, Kotseva K, Mirrakhimov E, Reiner Ž, Rydén L, et al. disease prevention in clinical practice: the sixth joint task force of the European Management of dyslipidaemia in patients with coronary heart disease: results from society of cardiology and other societies on cardiovascular disease prevention the ESC-EORP EUROASPIRE V survey in 27 countries. Atherosclerosis. (2019) in clinical practice (constituted by representatives of 10 societies and by invited 285:135–46. doi: 10.1016/j.atherosclerosis.2019.03.014 experts). Developed with the special contribution of the European association for cardiovascular prevention & rehabilitation (EACPR). Eur Heart J. (2016) 6. Leskelä RL, Torvinen A, Rissanen TT, Virtanen V, Herse F, Nuutinen M, et al. 37:2315–81. doi: 10.1093/eurheartj/ehw106 Outcomes of lipid control in secondary prevention of coronary artery disease in Finland: a 24-month follow-up after acute coronary syndrome. Atherosclerosis. 16. Schiele F, Farnier M, Krempf M, Bruckert E, Ferrières J. A consensus (2020) 296:4–10. doi: 10.1016/j.atherosclerosis.2020.01.018 statement on lipid management after acute coronary syndrome. Eur Heart J Acute Cardiovasc Care. (2018) 7:532–43. doi: 10.1177/2048872616679791 7. Lázaro P, Murga N, Aguilar D, Hernández-Presa MA. Therapeutic inertia in the outpatient management of dyslipidemia in patients with ischemic heart disease. 17. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. The inertia study. Rev Esp Cardiol. (2010) 63:1428–37. doi: 10.1016/s1885-5857(10) 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification 70277-2 to reduce cardiovascular risk. Eur Heart J. (2020) 41:111–88. doi: 10.1093/eurheartj/ ehz455 8. Fitzsimons D, Stȩpińska J, Kerins M, Piepoli MF, Hill L, Nuutinen M, et al. Secondary prevention and cardiovascular care across Europe: a survey of European 18. Vrablik M, Seifert B, Parkhomenko A, Banach M, Jóźwiak JJ, Kiss RG, et al. society of cardiology members’ views. Eur J Cardiovasc Nurs. (2020) 19:201–11. Lipid-lowering therapy use in primary and secondary care in central and Eastern doi: 10.1177/1474515119877999 Europe: DA VINCI observational study. Atherosclerosis. (2021) 334:66–75. doi: 10.1016/j.atherosclerosis.2021.08.035 9. Akter S, Roy P. mHealth – an ultimate platformto serve the unserved. Yearbook Med Inform. (2010) 1:94–100. 19. Cannon CP, de Lemos JA, Rosenson RS, Ballantyne CM, Liu Y, Gao Q, et al. Use of lipid-lowering therapies over 2 years in GOULD, a registry of patients 10. Akbari M, Lankarani KB, Naghibzadeh-Tahami A, Tabrizi R, Honarvar B, with atherosclerotic cardiovascular disease in the US. JAMA Cardiol. (2021) 6:1–9. Kolahdooz F, et al. The effects of mobile health interventions on lipid profiles doi: 10.1001/jamacardio.2021.1810 among patients with metabolic syndrome and related disorders: a systematic review and meta-analysis of randomized controlled trials. Diabetes Metab Syndr. (2019) 20. Navar AM, Wang TY, Li S, Robinson JG, Goldberg AC, Virani S, et al. 13:1949–55. doi: 10.1016/j.dsx.2019.04.011 Lipid management in contemporary community practice: results from the provider Frontiers in Cardiovascular Medicine 07 frontiersin.org Ruiz-Bustillo et al. 10.3389/fcvm.2022.916031 assessment of lipid management (PALM) registry. Am Heart J. (2017) 193:84–92. 25. Elamin AFM, Grafton-Clarke C, Chen KW, Obafemi T, Luvai A, Katira R, doi: 10.1016/j.ahj.2017.08.005 et al. Potential use of PCSK9 inhibitors as a secondary preventative measure for cardiovascular disease following acute coronary syndrome: a UK real-world study. 21. Postmus I, Trompet S, Deshmukh HA, Barnes MR, Jóźwiak JJ, Kiss RG, Postgrad Med J. (2019) 95:61–6. doi: 10.1136/postgradmedj-2018-136171 et al. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins. Nat Commun. (2014) 5:5068. doi: 10.1038/ 26. Furtado RHM, Giugliano RP. What lessons have we learned and what ncomms6068 remains to be clarified for PCSK9 inhibitors?. A review of FOURIER and ODYSSEY Outcomes Trials. Cardiol Ther. (2020) 9:59–73. doi: 10.1007/s40119-020-0 22. Ridker PM, Mora S, Rose L, Jupiter Trial Study Group. Percent reduction in 0163-w LDL cholesterol following high-intensity statin therapy: potential implications for guidelines and for the prescription of emerging lipid-lowering agents. Eur Heart J. 27. Howard JP, Wood FA, Finegold JA, Nowbar AN, Thompson DM, Arnold (2016) 37:1373–9. doi: 10.1093/eurheartj/ehw046 AD, et al. Side effect patterns in a crossover trial of statin, placebo, and no treatment. J Am Coll Cardiol. (2021) 78:1210–22. doi: 10.1016/j.jacc.2021. 23. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy 07.022 SA, et al. FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. (2017) 28. Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, et al. 376:1713–22. doi: 10.1056/NEJMoa1615664 Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. (2016) 388:2532–61. doi: 10.1016/S0140-6736(16)31357-5 24. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. ODYSSEY OUTCOMES committees and Investigators. Alirocumab and 29. Jakobsson S, Irewall AL, Bjorklund F, Mooe T. Cardiovascular secondary cardiovascular outcomes after acute coronary syndrome. N Engl J Med. (2018) prevention in high-risk patients: a randomized controlled trial sub-study. BMC 379:2097–107. doi: 10.1056/NEJMoa1801174 Cardiovasc Disord. (2015) 15:125. doi: 10.1186/s12872-015-0115-0 Frontiers in Cardiovascular Medicine 08 frontiersin.org