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      Cardiovascular Outcomes and Mortality Associated With Discontinuing Statins in Older Patients Receiving Polypharmacy

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          Key Points

          Question

          What are the clinical implications of statin discontinuation in older patients receiving polypharmacy?

          Findings

          In this population-based cohort study of 29 047 patients, there was evidence that discontinuing therapy with statins was associated with a significantly increased risk of hospital admission for heart failure and any cardiovascular outcome, death from any cause, and emergency admission for any cause.

          Meaning

          The findings of this study suggest that discontinuing statins while maintaining other drug therapies may increase the long-term risk of fatal and nonfatal cardiovascular outcomes.

          Abstract

          This population-based cohort study assesses the clinical implications of discontinuing the use of statins while maintaining other drugs in a cohort of older patients receiving polypharmacy.

          Abstract

          Importance

          Polypharmacy is a major health concern among older adults. While deprescribing may reduce inappropriate medicine use, its effect on clinical end points remains uncertain.

          Objective

          To assess the clinical implications of discontinuing the use of statins while maintaining other drugs in a cohort of older patients receiving polypharmacy.

          Design, Setting, and Participants

          This retrospective, population-based cohort study included the 29 047 residents in the Italian Lombardy region aged 65 years or older who were receiving uninterrupted treatment with statins, blood pressure–lowering, antidiabetic, and antiplatelet agents from October 1, 2013, until January 31, 2015, with follow-up through June 30, 2018. Data were collected using the health care utilization database of Lombardy region in Italy. Data analysis was conducted from March to November 2020.

          Exposures

          Cohort members were followed up to identify those who discontinued statins. Among this group, those who maintained other therapies during the first 6 months after statin discontinuation were 1:1 propensity score matched with patients who discontinued neither statins nor other drugs.

          Main Outcome and Measures

          The pairs of patients discontinuing and maintaining statins were followed up from the initial discontinuation until June 30, 2018, to estimate the hazard ratios (HRs) and 95% CIs for fatal and nonfatal outcomes associated with statin discontinuation.

          Results

          The full cohort inclued 29 047 patients exposed to polypharmacy (mean [SD] age, 76.5 [6.5] years; 18 257 [62.9%] men). Of them, 5819 (20.0%) discontinued statins while maintaining other medications, and 4010 (68.9%) of them were matched with a comparator. In the discontinuing group, the mean (SD) age was 76.5 (6.4) years, 2405 (60.0%) were men, and 506 (12.6%) had Multisource Comorbidity Scores of 4 or 5. In the maintaining group, the mean (SD) age was 76.1 (6.3) years, 2474 (61.7%) were men, and 482 (12.0%) had multisource comorbidity scores of 4 or 5. Compared with the maintaining group, patients in the discontinuing group had increased risk of hospital admissions for heart failure (HR, 1.24; 95% CI, 1.07-1.43) and any cardiovascular outcome (HR, 1.14; 95% CI, 1.03-1.26), deaths from any cause (HR, 1.15; 95% CI, 1.02-1.30), and emergency admissions for any cause (HR, 1.12; 95% CI, 1.05-1.19).

          Conclusions and Relevance

          In this study of patients receiving polypharmacy, discontinuing statins while maintaining other drug therapies was associated with an increase in the long-term risk of fatal and nonfatal cardiovascular outcomes.

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          Most cited references51

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          The central role of the propensity score in observational studies for causal effects

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            Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials

            Summary Background Lowering of LDL cholesterol with standard statin regimens reduces the risk of occlusive vascular events in a wide range of individuals. We aimed to assess the safety and efficacy of more intensive lowering of LDL cholesterol with statin therapy. Methods We undertook meta-analyses of individual participant data from randomised trials involving at least 1000 participants and at least 2 years' treatment duration of more versus less intensive statin regimens (five trials; 39 612 individuals; median follow-up 5·1 years) and of statin versus control (21 trials; 129 526 individuals; median follow-up 4·8 years). For each type of trial, we calculated not only the average risk reduction, but also the average risk reduction per 1·0 mmol/L LDL cholesterol reduction at 1 year after randomisation. Findings In the trials of more versus less intensive statin therapy, the weighted mean further reduction in LDL cholesterol at 1 year was 0·51 mmol/L. Compared with less intensive regimens, more intensive regimens produced a highly significant 15% (95% CI 11–18; p<0·0001) further reduction in major vascular events, consisting of separately significant reductions in coronary death or non-fatal myocardial infarction of 13% (95% CI 7–19; p<0·0001), in coronary revascularisation of 19% (95% CI 15–24; p<0·0001), and in ischaemic stroke of 16% (95% CI 5–26; p=0·005). Per 1·0 mmol/L reduction in LDL cholesterol, these further reductions in risk were similar to the proportional reductions in the trials of statin versus control. When both types of trial were combined, similar proportional reductions in major vascular events per 1·0 mmol/L LDL cholesterol reduction were found in all types of patient studied (rate ratio [RR] 0·78, 95% CI 0·76–0·80; p<0·0001), including those with LDL cholesterol lower than 2 mmol/L on the less intensive or control regimen. Across all 26 trials, all-cause mortality was reduced by 10% per 1·0 mmol/L LDL reduction (RR 0·90, 95% CI 0·87–0·93; p<0·0001), largely reflecting significant reductions in deaths due to coronary heart disease (RR 0·80, 99% CI 0·74–0·87; p<0·0001) and other cardiac causes (RR 0·89, 99% CI 0·81–0·98; p=0·002), with no significant effect on deaths due to stroke (RR 0·96, 95% CI 0·84–1·09; p=0·5) or other vascular causes (RR 0·98, 99% CI 0·81–1·18; p=0·8). No significant effects were observed on deaths due to cancer or other non-vascular causes (RR 0·97, 95% CI 0·92–1·03; p=0·3) or on cancer incidence (RR 1·00, 95% CI 0·96–1·04; p=0·9), even at low LDL cholesterol concentrations. Interpretation Further reductions in LDL cholesterol safely produce definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke, with each 1·0 mmol/L reduction reducing the annual rate of these major vascular events by just over a fifth. There was no evidence of any threshold within the cholesterol range studied, suggesting that reduction of LDL cholesterol by 2–3 mmol/L would reduce risk by about 40–50%. Funding UK Medical Research Council, British Heart Foundation, European Community Biomed Programme, Australian National Health and Medical Research Council, and National Heart Foundation.
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              Renin–Angiotensin–Aldosterone System Blockers and the Risk of Covid-19

              Abstract Background A potential association between the use of angiotensin-receptor blockers (ARBs) and angiotensin-converting–enzyme (ACE) inhibitors and the risk of coronavirus disease 2019 (Covid-19) has not been well studied. Methods We carried out a population-based case–control study in the Lombardy region of Italy. A total of 6272 case patients in whom infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed between February 21 and March 11, 2020, were matched to 30,759 beneficiaries of the Regional Health Service (controls) according to sex, age, and municipality of residence. Information about the use of selected drugs and patients’ clinical profiles was obtained from regional databases of health care use. Odds ratios and 95% confidence intervals for associations between drugs and infection, with adjustment for confounders, were estimated by means of logistic regression. Results Among both case patients and controls, the mean (±SD) age was 68±13 years, and 37% were women. The use of ACE inhibitors and ARBs was more common among case patients than among controls, as was the use of other antihypertensive and non-antihypertensive drugs, and case patients had a worse clinical profile. Use of ARBs or ACE inhibitors did not show any association with Covid-19 among case patients overall (adjusted odds ratio, 0.95 [95% confidence interval {CI}, 0.86 to 1.05] for ARBs and 0.96 [95% CI, 0.87 to 1.07] for ACE inhibitors) or among patients who had a severe or fatal course of the disease (adjusted odds ratio, 0.83 [95% CI, 0.63 to 1.10] for ARBs and 0.91 [95% CI, 0.69 to 1.21] for ACE inhibitors), and no association between these variables was found according to sex. Conclusions In this large, population-based study, the use of ACE inhibitors and ARBs was more frequent among patients with Covid-19 than among controls because of their higher prevalence of cardiovascular disease. However, there was no evidence that ACE inhibitors or ARBs affected the risk of COVID-19.
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                Author and article information

                Journal
                JAMA Netw Open
                JAMA Netw Open
                JAMA Netw Open
                JAMA Network Open
                American Medical Association
                2574-3805
                14 June 2021
                June 2021
                14 June 2021
                : 4
                : 6
                : e2113186
                Affiliations
                [1 ]National Centre for Healthcare Research and Pharmacoepidemiology, University of Milano-Bicocca, Milan, Italy
                [2 ]Laboratory of Healthcare Research and Pharmacoepidemiology, Unit of Biostatistics, Epidemiology, and Public Health, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy
                [3 ]Department of Medicine, Surgery, and Dentistry, University of Salerno, Baronissi, Italy
                [4 ]LinkHealth, Health Economics, Outcomes and Epidemiology, Naples, Italy
                Author notes
                Article Information
                Accepted for Publication: April 6, 2021.
                Published: June 14, 2021. doi:10.1001/jamanetworkopen.2021.13186
                Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Rea F et al. JAMA Network Open.
                Corresponding Author: Annalisa Biffi, PhD, Laboratory of Healthcare Research and Pharmacoepidemiology, Division of Biostatistics, Epidemiology, and Public Health, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Street Bicocca degli Arcimboldi, 8, Building U7, 20126 Milan, Italy ( annalisa.biffi@ 123456unimib.it ).
                Author Contributions: Drs Rea and Biffi had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
                Concept and design: Rea, Biffi, Filippelli, Corrao.
                Acquisition, analysis, or interpretation of data: Rea, Biffi, Ronco, Franchi, Cammarota, Citarella, Conti, Sellitto, Corrao.
                Drafting of the manuscript: Conti, Filippelli, Sellitto, Corrao.
                Critical revision of the manuscript for important intellectual content: Rea, Biffi, Ronco, Franchi, Cammarota, Citarella.
                Statistical analysis: Rea, Biffi, Ronco, Franchi, Corrao.
                Obtained funding: Corrao.
                Administrative, technical, or material support: Sellitto.
                Supervision: Filippelli, Corrao.
                Conflict of Interest Disclosures: Dr Corrao reported serving on the advisory board of Roche and receiving grants from Bristol Myers Squibb, GlaxoSmithKline, and Novartis outside the submitted work. No other disclosures were reported.
                Funding/Support: This study was funded by grant 2019-ATE-0607 (Fondo d’Ateneo per la Ricerca) and grant H45J17000500006 (Modelling Effectiveness, Cost-effectiveness, and Promoting Health Care Value in the Real World: the Motive Project) from the Italian Ministry of the Education, University and Research.
                Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
                Additional Information: The data that support the findings of this study are available from Lombardy Region, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the Lombardy Region on reasonable request.
                Article
                zoi210393
                10.1001/jamanetworkopen.2021.13186
                8204202
                34125221
                2eae0e2b-d7ab-48d0-86c5-a28fa67568c0
                Copyright 2021 Rea F et al. JAMA Network Open.

                This is an open access article distributed under the terms of the CC-BY License.

                History
                : 4 January 2021
                : 6 April 2021
                Categories
                Research
                Original Investigation
                Online Only
                Pharmacy and Clinical Pharmacology

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