Cardiovascular drug use after myocardial infarction : adherence, kidney dysfunction, and real-world outcomes

<p dir="ltr">Patients with acute coronary syndromes (ACS) face a substantial risk of recurrent events and mortality, particularly at higher age or when chronic kidney disease (CKD) is present. Several factors may contribute to this elevated risk, including suboptimal prescription, initiation, and adherence to guideline-recommended secondary prevention therapies. This thesis utilized merged real-world data from national and regional sources, including the nationwide Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease (SWEDEHEART) registry, the Stockholm Creatinine Measurements (SCREAM) database, and the National Prescribed Drug Register. Its main objective was to examine secondary prevention drug use and long-term outcomes after ACS or acute myocardial infarction (AMI) in various contexts, with a specific focus on patients with CKD.</p><p dir="ltr">Study I assessed the relationship between kidney function and use of key secondary prevention drugs among ACS survivors. All patients admitted with a first ACS enrolled in SWEDEHEART between 2005-2010 were identified. After excluding those who died in-hospital or lacked serum creatinine data, 75,129 patients remained to analyze. Following adjustment for absolute or relative contraindications, patients with moderately reduced kidney function (eGFR 30-59 mL/min/1.73 m²) less frequently received acetylsalicylic acid, statins, and ß-blockers compared with those with normal-mildly reduced kidney function (eGFR ≥60 mL/min/1.73 m²). They were also more likely to discontinue acetylsalicylic acid (hazard ratio [HR] 1.49, 95% CI 1.42-1.56), statins (HR 1.35, 95% CI 1.29-1.41), renin-angiotensin system inhibitors (HR 1.37, 95% CI 1.31-1.43), and ß-blockers (HR 1.22, 95% CI 1.18-1.27) during the first year post-event. Patients with severely reduced kidney function (eGFR <30 mL/min/1.73 m²) exhibited similar patterns in both prescription and discontinuation.</p><p dir="ltr">Study Il investigated the association between adherence to ß-blocker therapy after a first AMI and long-term risk of death or readmission due to heart failure (HF). Among 38,608 patients admitted for a first AMI between 2005-2010 enrolled in SWEDEHEART, those who died within the first year, had prior HF, or unknown ejection fraction (EF) were excluded. Adherence was defined as a proportion of days covered 280% at one year. Patients with reduced EF, regardless of in-hospital signs of HF, were more likely to stay adherent to ß-blocker therapy than those with normal EF and no HF. Socioeconomic and clinical factors were associated with better adherence. The whole group of patients with reduced kidney function showed a non-significant trend toward non-adherence, while dialysis was clearly associated with non-adherence. In adjusted analyses, adherence was associated with reduced all-cause mortality (HR 0.77, 95% CI 0.71-0.84) over four years, though this benefit was not statistically significant in patients with normal EF irrespectively of heart failure status. Adherence was also associated with reduced risk of the composite outcome of HF readmission/death in all patients (HR 0.83, 95% CI 0.78-0.89), but the association was uncertain in subgroups with normal EF with and without heart failure signs.</p><p dir="ltr">Study III examined the association between statin intensity and long-term outcomes, focusing on patients with CKD. Among 112,727 patients admitted for a first AMI enrolled in SWEDEHEART between 2005-2016, those who died in-hospital, lacked creatinine data, or did not initiate statin therapy within 90 days were excluded. High-intensity statins were initiated in 38.7% of patients, while 61.3% received low-moderate intensity. Among one-year survivors, statin discontinuation in CKD patients was 25%, with similar rates across intensity groups. After further exclusions for death, therapy switch, or non-adherence at one year, 84,705 patients remained for on-treatment analysis. In patients with moderately reduced kidney function, high-intensity statins were associated with a reduced risk of death, reinfarction, or stroke in both intention-to-treat (HR 0.93, 95% CI 0.87-0.99) and on-treatment analyses (HR 0.90, 95% CI 0.83-0.99), with no evidence of heterogeneity across kidney function groups (P = 0.46).</p><p dir="ltr">Study IV compared patient characteristics, clinical management, and long-term outcomes between AMI patients enrolled in SWEDEHEART and those not enrolled. Using a regional database (SCREAM), 47,342 AMI hospitalizations (40,935 incident cases) were identified between 2006-2021 in the region of Stockholm. Enrolment was defined as having any record in the Register of Information and Knowledge About Swedish Heart Intensive Care Admissions (RIKS-HIA), a sub register of SWEDEHEART, during the index hospitalization or within one day prior to admission, to account for emergency department registrations. Non-enrolled patients (N = 6,113; 13%) were older, more often had CKD, and had a higher comorbidity burden and frailty risk. They were less likely to undergo invasive procedures and initiate acetylsalicylic acid (HR 0.88, 95% CI 0.84-0.91), ß-blockers (HR 0.87, 95% CI 0.84-0.90), renin-angiotensin system inhibitors (HR 0.73, 95% CI 0.69-0.76), or statins (HR 0.59, 95% CI 0.56-0.61). Adherence during the first year was also lower, partly due to their comorbidity profile. Non-enrolled patients experienced higher in-hospital and long-term mortality (HR 1.15, 95% CI 1.09-1.21) and more reinfarction or stroke (HR 1.16, 95% Cl 1.08-1.26) compared with enrolled patients.</p><p dir="ltr">Conclusions: Patients with ACS and CKD were less frequently prescribed secondary prevention drugs at discharge and, when initiated, more likely to discontinue within the first year. Adherence to ß-blockers after AMI was associated with improved long-term outcomes, though this benefit may be limited to patients with reduced ejection fraction. High-intensity statin therapy in CKD patients was associated with better long-term outcomes after AMI. Most patients with CKD that started on high-intensity statins remained on this regimen after one year, with overall persistence to statin treatment equal to those that started on low-moderate intensity therapy. Patients not enrolled in SWEDEHEART were less likely to receive guideline-recommended treatments and had worse short- and long-term outcomes. Although overall improvements in adherence to guideline-recommendations have been observed over the years, these findings highlight persistent gaps in cardiovascular care that warrant further studies and interventions.</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Khedri M,</b> Szummer K, Carrero JJ, Jernberg T, Evans M, Jacobson SH, Spaak J. Systematic underutilisation of secondary preventive drugs in patients with acute coronary syndrome and reduced renal function. Eur J Prev Cardiol. 2017 May;24(7):724-734. <a href="https://doi.org/10.1177/2047487317693950" target="_blank">https://doi.org/10.1177/2047487317693950</a></p><p dir="ltr">II. Desta L*, <b>Khedri M*</b>, Jernberg T, Andell P, Mohammad MA, Hofman-Bang C, Erlinge D, Spaak J^§, Persson H^§. Adherence to beta-blockers and long-term risk of heart failure and mortality after a myocardial infarction. ESC Heart Fail. 2021 Feb;8(1):344-355. <a href="https://doi.org/10.1002/ehf2.13079" target="_blank">https://doi.org/10.1002/ehf2.13079</a></p><p dir="ltr">III. <b>Khedri M,</b> Szummer K, Lundman P, Jernberg T, Desta L, Lindahl B, Erlinge D, Jacobson SH, Spaak J. Statin Treatment Intensity, Discontinuation, and Long-Term Outcome in Patients With Acute Myocardial Infarction and Impaired Kidney Function. J Cardiovasc Pharmacol. 2023 Jun 1;81(6):400-410. <a href="https://doi.org/10.1097/FJC.0000000000001402" rel="noreferrer" target="_blank">https://doi.org/10.1097/FJC.0000000000001402</a></p><p dir="ltr">IV. <b>Khedri M,</b> Szummer K, Jacobson SH, Hjemdahl P, Spaak J^§. Carrero JJ^§. Characteristics, clinical management and outcomes of patients with acute myocardial infarction enrolled or not enrolled in a quality registry. [Submitted]</p><p dir="ltr">*Contributed equally to the work.</p><p dir="ltr">§Share senior authorship of the work.</p>