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Optimal Medical Therapy Prescription in Patients with Acute Coronary Syndrome in the Netherlands: A Multicenter Pilot Registry

Optimal Medical Therapy Prescription in Patients with Acute Coronary Syndrome in the Netherlands:... Background Unlike neighboring countries, the Netherlands does not have a national acute coronary syndrome (ACS) registry to evaluate quality of care. Objective We conducted a pilot registry in two hospitals to assess the prescription of guideline-recommended therapies in Dutch patients with ACS. Methods We included all consecutive patients with ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) (n = 1309) admitted to two Dutch percutaneous coronary intervention centers between March 2015 and February 2016. We collected follow-up medication use and reasons for discontinuation at discharge and 1, 6, and 12 months post-discharge. We assessed the use of optimal medical therapy (OMT), defined as the combined prescription of aspirin, P2Y12 inhibitors, statins, β-blockers, and angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. Results OMT prescription was 43.2% at discharge, 60.1% at 1 month, and 28.7% at 12 months. At 1 month, OMT prescrip- tion was significantly lower in patients with NSTEMI (51.8 vs. 65.7% for STEMI; p < 0.001). OMT prescription was lower in women (6 months: 55.4 vs. 62.0%, p = 0.036) and in elderly patients. Conclusion In this pilot study that aimed to extend a national Dutch ACS registry to patients with STEMI and NSTEMI, OMT prescription was comparable to that in other local registries, was lower in women and patients with NSTEMI, and decreased with increasing age. 1 Introduction and those with non-ST-segment elevation myocardial infarc- tion (NSTEMI) [1, 2]. During the last two decades, the development of invasive and Guideline-recommended therapies in patients with acute medical therapies has improved outcomes in both patients coronary syndrome (ACS) include invasive treatments such with ST-segment elevation myocardial infarction (STEMI) as coronary angiography with subsequent percutaneous cor- onary intervention (PCI) or coronary artery bypass grafting Electronic supplementary material The online version of this (CABG) and optimal medical therapy (OMT) [3, 4]. OMT article (https ://doi.org/10.1007/s4025 6-020-00427 -9) contains consists of aspirin, P2Y12 inhibitor, statin, β-blocker, and an supplementary material, which is available to authorized users. angiotensin-converting enzyme inhibitor (ACEi) or angio- * Niels P. G. Hoedemaker tensin-receptor blocker (ARB). β-blockers and ACEi/ARBs n.p.g.hoedemaker@olvg.nl have a class IA recommendation in patients with ACS with a reduced left ventricular ejection fraction (LVEF ≤ 40%) [3, Heart Center, Department of Cardiology, Amsterdam 4]. Dual therapy with a P2Y12 inhibitor and a coumarin or Cardiovascular Sciences, Amsterdam UMC, Location AMC, University of Amsterdam, Meibergdreef 9, novel oral anticoagulant (NOAC) as a replacement for aspi- 1105 AZ Amsterdam, The Netherlands rin is also considered OMT. Additionally, prescription of a Department of Cardiology, Maastricht University Medical proton pump inhibitor (PPI) is recommended in patients with Center, Maastricht, The Netherlands ACS aged ≥ 65 years receiving dual antiplatelet therapy Diagram B.V, Zwolle, The Netherlands (DAPT) and NOACs [5]. National registries in Denmark, Sweden, and the UK Department of Cardiology, Isala Klinieken, Zwolle, The Netherlands have contributed to improve adherence to the abovemen- tioned guideline-recommended therapies, which has been Department of Cardiology, Radboud University Medical Center, Nijmegen, The Netherlands linked to an overall benefit for patients with ACS [6 –8]. Vol.:(0123456789) 220 N. P. G. Hoedemaker et al. until 29 February 2016. Patients were diagnosed if they had KeyPoints ischemic symptoms lasting > 20 min and elevated cardiac biomarkers and/or new ST-segment elevation in two contigu- Guideline-recommended optimal medical therapy ous leads, left bundle branch block, ST-T or T-wave changes, (OMT) for secondary prevention after acute coronary or Q-waves on a 12-lead electrocardiogram. Only patients syndrome (ACS) consists of aspirin, P2Y12 inhibitors, with type 1 myocardial infarction (MI) according to the statins, β-blockers, and angiotensin-converting enzyme Third Universal Definition of MI were included [10]. Any inhibitors or angiotensin-receptor blockers. discrepancies on the assessment of MI type were discussed until consensus was reached. Most European countries have a national ACS registry, which has contributed to improving adherence to OMT; 2.3 Treatment however, the Netherlands does not have a national ACS registry. The preferred treatment strategy in patients with STEMI In this multicenter pilot registry of two Dutch hospitals, was primary PCI. In patients with NSTEMI, the timing and OMT use was significantly lower among patients with performance of angiography and revascularization were in non-ST-elevation myocardial infarction, women, and accordance with the European guidelines [3, 4]. Patients elderly patients. undergoing angiography were pretreated with aspirin, hepa- rin, and a P2Y12 inhibitor (ticagrelor 180 mg or clopidogrel Similar findings were observed in other registry studies, 600 mg loading dose). CABG was performed if indicated. so further efforts to improve OMT use should focus on Prescription of guideline-recommended therapies and refer- these subgroups. ral to cardiac rehabilitation was in accordance with the 2012 STEMI and 2015 NSTE-ACS guidelines from the European However, the Netherlands does not have a national ACS Society of Cardiology (ESC) and was encouraged in all registry. A report by the National Cardiovascular Database patients [3, 4]. Registry (NCDR) demonstrated the feasibility of a Dutch ACS registry but only enrolled patients with STEMI over a 2.4 Data Collection and Follow‑Up 4-week period [9]. The current study is a pilot study from two Dutch PCI centers that aimed to expand the NCDR reg- Data were prospectively recorded in a dedicated case report istry by including both patients with STEMI and those with form using an anonymized patient identification number. NSTEMI over a full year of enrollment. We assessed the Variables included demographics, risk factors, medical his- prescription of guideline-recommended medical therapies tory, procedural characteristics, LVEF measured by echocar- and reasons for drug discontinuation after ACS. diography, and medication prescription at discharge and 1, 6, and 12 months post-discharge. We collected follow-up data on medication prescription and (at one center) discontinu- 2 Methods ation from hospital records and/or via telephone interviews with a trained research physician at 1, 6, and 12 months. 2.1 Study Setting and Design We obtained vital status from the Dutch national population registry. The two datasets were collected and merged for This study combines ACS registries from two PCI centers analysis at the AMC in Amsterdam. This study was con- in the Netherlands: the Academic Medical Centre (AMC) ducted with a waiver from the medical ethical committee of in Amsterdam and Isala Hospital Zwolle. Both centers the AMC in Amsterdam. According to Dutch law applicable recorded their own separate prospective observational reg- at the time of the study period, written informed consent for istries, based on the variable set of the NCDR, the predeces- the conduct of this registry study was not required. sors of the current Netherlands Heart Registry (NHR). The NHR was established in 2017, 1 year after the enrollment of 2.5 Definitions and Outcomes this study was completed. Representatives from both centers agreed to combine the two registries with the aim to assess The main outcome of this study was OMT at discharge and medication prescription. during follow-up. OMT was defined as a combination of aspirin, P2Y12 inhibitor, statin, β-blocker, and ACEi/ARB. 2.2 Patients Prescription of dual therapy (P2Y12 inhibitor with a NOAC) with a statin, β-blocker, and ACEi/ARB was also regarded We enrolled all consecutive patients with STEMI or as OMT. We assessed OMT prescription stratified by ACS NSTEMI admitted to our hospitals from 1 March 2015 type (STEMI vs. NSTEMI), sex, and age. We also evaluated Optimal Medical Therapy After Acute Coronary Syndrome 221 OMT, β-blocker, and ACEi/ARB prescription in patients coronary angiography (94.9%), and 81.8% of the patients with a preserved (> 40%) or reduced (≤ 40%) LVEF. Fur- were treated with PCI. PCI performance was significantly thermore, we evaluated prescriptions among patients with higher among patients with STEMI than those with NSTEMI a class IA indication for ACEi/ARBs and in patients with (90.7 vs. 62.8%; p < 0.001). CABG was performed in 7.3% STEMI (LVEF ≤ 40%, hypertension, diabetes mellitus, ante- of patients. rior MI) or NSTEMI (LVEF ≤ 40%, hypertension, diabetes mellitus) [3, 4]. We assessed the duration of DAPT prescrip-3.2 Mortality Outcome tion follow-up and switching between novel P2Y12 inhibi- tors (ticagrelor or prasugrel) and clopidogrel. Finally, we Vital status from the Dutch national population registry at 1 evaluated PPI prescriptions among patients receiving DAPT year was obtained for 1300 patients (99.3%). Nine patients or a NOAC and aged ≥ 65 years [5]. were not registered as inhabitants of the Netherlands so their vital status could not be obtained. In-hospital mortality was 2.6 Statistical Analysis 3.7%, 30-day mortality 4.5%, and 1-year mortality 7.4%. Continuous variables are presented as mean and standard 3.3 Medication at Discharge and During Follow‑Up deviation or as median and interquartile range (IQR) for nor- mal and skewed distributions, respectively. All categorical A flow chart of patients recruited and lost to medication variables are presented as absolute frequencies and percent- follow-up is provided in the Electronic Supplementary Mate- ages. Differences between groups were evaluated using the rial (ESM; Tables 4 and 5). Prescription of medication cat- unpaired t test or Mann–Whitney test (nonparametric) for egories is displayed in Table 2. Prescription at discharge continuous variables and the χ test for categorical variables. was highest for aspirin (88.8%), statins (86.6%), and P2Y12 The linear-by-linear association test was used to evaluate dif- inhibitors (84.8%). Prescription rates increased at 1 month ferences between age groups. We identified variables asso- but decreased at 6 and 12 months. Combined prescription of ciated with OMT prescription at discharge and 12-month medication is presented in Table 3. OMT prescription at dis- follow-up based on differences in baseline characteristics charge was 43.2%, increased to 60.1% at 1 month, and was and variables of interest according to guideline recommen- 50.8% and 28.7% at 6 and 12 months, respectively. Patients dations. We calculated odds ratios (ORs) and adjusted ORs not receiving OMT at discharge had a significantly shorter based on univariate and multivariate logistic regression admission length than did those receiving OMT (1.0 days models, respectively. All variables identified (age ≥65 years, [IQR 0.0–5.0] vs. 3.0 [IQR 1.0–5.0]; p < 0.001). OMT pre- female sex, hypertension, diabetes mellitus, hypercholester- scription at discharge and 1 and 6 months was higher among olemia, chronic kidney disease [creatinine clearance ≤ 50 patients with a reduced ejection fraction, but this was not ml/min], previous MI, previous CABG, previous stroke, statistically significant (Fig.  1a). STEMI, PCI performance, and CABG performance) were used in the multivariate model. A p value of < 0.05 (two-3.4 Antiplatelet Therapy sided) was considered statistically significant. All analyses were performed using SPSS version 25.0. Ticagrelor was the most prescribed P2Y12 inhibitor, with 58.9% of patients receiving it at discharge, whereas 25.3% of the patients received clopidogrel and < 1% received prasu- 3 Results grel. At discharge, 79.9% of patients received DAPT and 4.0% received dual therapy (NOAC and P2Y12 inhibitor). Between March 2015 and February 2016, a total of 1309 This decreased to 43.0% DAPT and 7.0% dual therapy at patients with ACS were included in the registry: 528 (40.3%) 12 months. Complete 12-month follow-up on DAPT pre- from the Amsterdam registry and 781 (59.7%) from the scription was available in 715 patients (54.6%). In total, 52 Zwolle registry. patients (7.3%) stopped using DAPT between discharge and 1 month, 12.9% stopped between 1 and 6 months, and 33.0% 3.1 Baseline and Procedural Characteristics stopped between 6 and 12 months. Approximately half of the patients (46.9%) received DAPT for at least 12 months. Table 1 displays the baseline and procedural characteristics. From discharge until 1 month, 28 patients (3.6%) switched The mean age was 64.9 years, and 28.6% of the patients were from a novel P2Y12 inhibitor to clopidogrel, and 14 patients women (Table 1). Hypertension was present in 45.6%, and (1.8%) switched to a novel P2Y12 inhibitor. Between 1 and 17.2% had diabetes mellitus. Approximately two-thirds of 6 months, 36 patients (4.5%) switched to clopidogrel, and patients were admitted with STEMI (64.6%) and one-third nine patients (1.1%) switched to a novel P2Y12 inhibitor. with NSTEMI (35.4%). The majority of patients underwent Between 6 and 12 months, 23 patients (2.4%) switched 222 N. P. G. Hoedemaker et al. from a novel P2Y12 inhibitor to clopidogrel, and three Table 1 Baseline characteristics patients (0.3%) switched from clopidogrel to a novel P2Y12 Characteristics Overall (n = 1309) inhibitor. Demographics Age, years 64.9 ± 12.7 3.5 β‑Blockers, Angiotensin‑Converting Enzyme Women 374/1309 (28.6) Inhibitors, and Angiotensin‑Receptor Blockers Risk factors According to Ejection Fraction Hypertension 578/1268 (45.6) Diabetes mellitus 218/1270 (17.2) β-blocker prescription at discharge was similar for patients  Smoking status with preserved or reduced LVEF (82.4 vs. 81.1%; p = Current 435/1238 (35.1) 0.763). At 1, 6, and 12 months, β-blocker rates were higher Past smoker 170/1238 (13.7) among patients with reduced LVEF. ACEi/ARB prescription Never smoked 461/1238 (37.2) was markedly higher among patients with reduced LVEF. At Unknown 172/1238 (13.9) discharge, 63.7% of the patients with STEMI with a class IA Hypercholesterolemia 338/1255 (26.9) indication for ACEi/ARBs were treated according to ESC Family history of CVD 420/1156 (36.3) guidelines. This rate increased to 86.7%, 83.8%, and 81.9% Medical history at 1-, 6-, and 12-month follow-up, respectively. Among COPD 87/1054 (8.3) patients with NSTEMI with a class IA indication for ACEi/ Chronic kidney disease 105/1093 (9.6) ARBs, 72.4% were prescribed one of these drugs in accord- Previous MI 108/1093 (8.3) ance with the guidelines. This later increased to 79.3% at 1 Previous PCI 131/1309 (10.0) month, 75.5% at 6 months, and 74.7% at 12 months. Co-pre- Previous CABG 51/1309 (3.9) scription of a β-blocker and an ACEi/ARB in patients with Previous stroke 63/1063 (5.9) reduced LVEF was 62.1% at discharge, 77.5% at 1 month, Clinical presentation 71.8% at 6 months, and 70.0% at 12 months. Additional STEMI 845/1309 (64.6) results on combined prescriptions according to LVEF are NSTEMI 464/1309 (35.4) presented in Tables 2 and 3 in the ESM. Killip class > 2 60/436 (13.8) Cardiogenic shock 58/1309 (4.4) 3.6 Proton Pump Inhibitors OHCA 74/1309 (5.7) Invasive treatment during admission Among patients receiving DAPT, PPI prescription was Coronary angiography 1242/1309 (94.9) 73.7% and approximately 85% during follow-up (1 month, PCI 978/1195 (81.8) 86.4%; 6 months, 84.5%; and 12 months, 86.2%). PPI pre- Stent type scription was even higher for patients receiving NOACs: DES 784/853 (91.9) 84.1% at discharge and 91.4%, 89.0%, and 91.6% at 1, 6, and BMS 14/853 (1.6) 12 months, respectively. A PPI was prescribed in 79.3% of BVS 55/853 (6.4) patients aged ≥ 65 years at discharge and in 93.2%, 90.5%, CABG 87/1195 (7.3) and 89.5% at 1, 6, and 12-month follow-up. LVEF during admission Preserved (> 40%) 320/430 (74.4) 3.7 STEMI vs. NSTEMI Reduced (≤ 40%) 110/430 (25.6) Length of stay, days 2.0 (1.0–5.0) OMT at discharge was no different between patients with STEMI or NSTEMI (43.9 vs. 41.9%; p = 0.524; Fig. 1b). Data are presented as mean ± standard deviation, N (%), or median OMT prescription was significantly higher among patients (interquartile range) unless otherwise indicated with STEMI at 1 and 6 months (65.7 vs. 51.8%, p < 0.001 BMS bare metal stent, BVS bioresorbable scaffold, CABG coronary and 54.2 vs. 46.0%, p = 0.017, respectively). This difference artery bypass grafting, COPD chronic obstructive pulmonary dis- ease, CVD cardiovascular disease, DES drug-eluting stent, LVEF left was mainly because of higher rates of P2Y12 inhibitors and ventricular ejection fraction, MI myocardial infarction, NSTEMI non- ACEi/ARBs among patients with STEMI (Tables 4 and 5 in ST-segment elevation myocardial infarction, OHCA out-of-hospital the ESM). There were no differences in OMT at 12 months cardiac arrest, PCI percutaneous coronary intervention, STEMI ST- (28.5 vs. 29.0%, p = 0.891). segment elevation myocardial infarction Optimal Medical Therapy After Acute Coronary Syndrome 223 Table 2 Medication at discharge 1, 6, and 12 months after acute coronary syndrome Timepoint Medication Overall (n = 1309) LVEF > 40% (n = 320) LVEF ≤ 40% (n = 110) p value Discharge Aspirin 986/1110 (88.8) P2Y12 inhibitor 941/1110 (84.8) Statin 958/1110 (86.3) β-blocker 860/1110 (77.5) 253/307 (82.4) 77/95 (81.1) 0.763 ACE inhibitor/ARB 676/1110 (60.9) 187/307 (60.9) 64/95 (67.4) 0.256 NOAC 164/1110 (14.8) PPI 806/1110 (72.6) 1 month Aspirin 870/961 (90.5) P2Y12 inhibitor 843/961 (87.7) Statin 897/960 (93.4) β-blocker 850/959 (88.6) 240/270 (88.9) 74/80 (92.5) 0.350 ACE inhibitor/ARB 750/957 (78.4) 194/270 (71.9) 66/80 (82.5) 0.056 NOAC 191/961 (19.9) PPI 804/934 (86.1) 6 months Aspirin 765/893 (85.7) P2Y12 inhibitor 726/893 (81.3) Statin 799/892 (89.6) β-blocker 738/890 (82.9) 216/266 (81.2) 66/71 (93.0) 0.017 ACE inhibitor/ARB 668/890 (75.1) 193/266 (72.6) 56/71 (78.9) 0.282 OAC 172/892 (19.3) PPI 745/889 (83.8) 12 months Aspirin 729/877 (83.1) P2Y12 inhibitor 452/876 (51.6) Statin 768/878 (87.5) β-blocker 675/876 (77.1) 209/264 (79.2) 60/70 (85.7) 0.219 ACE inhibitor/ARB 637/875 (72.8) 180/264 (68.2) 58/70 (82.9) 0.016 OAC 155/877 (17.7) PPI 714/875 (81.6) Data are presented as N (%) unless otherwise indicated ACE angiotensin-converting enzyme, ARB angiotensin-receptor blocker, LVEF left ventricular ejection fraction, NOAC novel oral anticoagula- tion, PPI proton pump inhibitor and PPI prescriptions increased with age (Tables 8 and 9 in 3.8 Sex Differences the ESM). Women had lower OMT prescription rates at discharge (45.9 3.10 Predictors of Optimal Medical Therapy (OMT) vs. 36.6%; p = 0.005) and during follow-up, but this was only significantly different at 6 months (62.0 vs. 55.4%; p = We performed univariate and multivariate logistic regres- 0.036; Fig. 1c). The differences can be explained by lower sion to identify predictors of OMT prescription at discharge rates of P2Y12 inhibitor and statin prescriptions among and 12-month follow-up (Table 10 in the ESM). Univariate women (Tables 6 and 7 in the ESM). predictors of OMT prescription at discharge were female sex and undergoing PCI or CABG. After multivariate adjust- 3.9 Age ment, female sex (OR 0.64; p = 0.007) and undergoing CABG (OR 0.35; p = 0.003) remained associated with OMT In general, OMT prescription decreased with age, both at prescription at discharge. Univariate predictors of OMT pre- discharge and during follow-up (Fig.  2). This decreasing scription at 12 months were female sex, previous stroke, and trend was significant at 1-month follow-up (p = 0.001). undergoing CABG. However, after multivariate adjustment, Figure  3 displays prescription rates for individual OMT only undergoing CABG remained independently associated medications according to age. The use of aspirin, P2Y12 with OMT prescription at discharge (OR 0.25; p = 0.007). inhibitors, and statins decreased with age, whereas NOAC 224 N. P. G. Hoedemaker et al. Table 3 Medication combinations at discharge and 1, 6, and 12 month after acute coronary syndrome Timepoint Medication Overall (n = 1309) LVEF > 40% (n = 320) LVEF ≤ 40% (n = 110) p value Discharge DAPT or dual therapy 929/1110 (83.7) DAPT 885/1110 (79.7) Dual therapy 44/1110 (4.0) DAPT or dual therapy and statin 842/1110 (75.9) DAPT and statin 807/1110 (72.7) Dual therapy and statin 35/1110 (3.2) OMT 479/1110 (43.2) 145/307 (47.2) 53/95 (55.8) 0.145 OMT with aspirin 458/1110 (41.3) 138/307 (45.0) 48/95 (50.5) 0.341 OMT with NOAC 21/1110 (1.9) 7/307 (2.3) 5/95 (5.3) 0.135 1 month DAPT or dual therapy 837/961 (87.1) DAPT 782/961 (81.4) Dual therapy 55/961 (5.7) DAPT or dual therapy and statin 790/960 (82.3) DAPT and statin 741/960 (77.2) Dual therapy and statin 49/960 (5.1) OMT 575/956 (60.1) 159/270 (58.9) 50/80 (62.5) 0.563 OMT with aspirin 540/956 (56.5) 150/270 (55.6) 44/50 (55.0) 0.930 OMT with NOAC 35/956 (3.7) 9/270 (3.3) 6/80 (7.5) 0.106 6 months DAPT or dual therapy 717/892 (80.4) DAPT 637/893 (71.3) Dual therapy 80/892 (9.0) DAPT or dual therapy and statin 651/891 (73.1) DAPT and statin 580/892 (65.0) Dual therapy and statin 71/891 (8.0) OMT 452/889 (50.8) 137/266 (51.5) 41/71 (57.7) 0.349 OMT with aspirin 394/889 (44.3) 113/266 (42.5) 33/71 (46.5) 0.546 OMT with NOAC 58/889 (6.5) 24/266 (9.0) 8/71 (11.3) 0.566 12 months DAPT or dual therapy 438/876 (50.0) DAPT 377/876 (43.0) Dual therapy 61/876 (7.0) DAPT or dual therapy and statin 391/876 (44.6) DAPT and statin 336/876 (38.4) Dual therapy and statin 55/876 (6.3) OMT 251/874 (28.7) 84/264 (31.8) 24/70 (34.3) 0.695 OMT with aspirin 209/874 (23.9) 65/264 (24.6) 20/70 (28.6) 0.500 OMT with NOAC 42/874 (4.8) 19/264 (7.2) 4/70 (5.7) 0.663 DAPT dual antiplatelet therapy, LVEF left ventricular ejection fraction, NOAC novel oral anticoagulation, OMT optimal medical therapy With regard to this result, we identified that P2Y12 inhibi- follows. First, 43.2%, of patients were discharged with OMT, tor use (37 vs. 89.5% at discharge and 25.4 vs. 54.1%) was which increased to 60.1% at 1 month and decreased to 28.7% significantly lower among patients who underwent CABG. at 12 months. Second, OMT prescription was numerically higher among patients with reduced LVEF, but this differ - ence was not statistically significant. Third, OMT prescrip- 4 Discussion tion was lower in patients with NSTEMI (at 1 and 6 months) and in women. Fourth, there was a decreasing trend in OMT In this study, we report adherence to guidelines in OMT prescription with increasing age. Finally, discontinuation prescriptions in consecutive patients with ACS from two PCI was highest for P2Y12 inhibitors (as per guidelines) and centers in the Netherlands. Our results can be summarized as ACEi/ARBs. Optimal Medical Therapy After Acute Coronary Syndrome 225 LVEF ACS Gender AB C 80 80 80 Preserved STEMI Men p=0.563 Reduced p<0.001 NSTEMI p=0.060 Women 70 p=0.349 70 p=0.017 70 p=0.036 65.7 p=0.145 62.5 p=0.524 p=0.005 62.0 58.9 60 57.7 60 60 55.8 55.4 54.2 53.1 51.5 51.8 50 47.2 50 50 46.0 45.9 45.3 43.9 p=0.695 p=0.891 p=0.281 41.9 40 40 40 36.6 34.3 31.8 29.8 29.0 28.5 30 30 30 26.1 20 20 20 10 10 10 0 0 0 Discharge1 month6 months 12 months Discharge1 month6 months 12 months Discharge 1 month6 months 12 months OMT prescription Fig. 1 Optimal medical therapy prescription at discharge, 1, 6, and 12 scription in patients with ACS with ST-elevation myocardial infarc- months in different subgroups. a optimal medical therapy (OMT) in tion (STEMI) or non-ST-segment elevation myocardial infarction patients with acute coronary syndrome (ACS) with a preserved ver- (NSTEMI). c displays differences in OMT prescription between men sus a reduced left ventricular ejection fraction (LVEF). b OMT pre- and women Fig. 2 Optimal medical therapy Age prescription at discharge, 1, 6, <45 and 12 months stratified by age. p=0.001 45−54 OMT optimal medical therapy 55−64 65−74 75−84 >84 60 p=0.086 p=0.230 40 p=0.646 Discharge 1 month6 months12 months OMT prescription PCI centers where early discharge and transfer back to the 4.1 Context and Interpretation referring regional non-PCI centers is common. This could explain why the median length of stay for patients without The discharge OMT prescription rate in our study (43.2%) OMT at discharge was 2 days shorter than those with OMT corresponds with that in a single-center registry study with and account for the observed increase in OMT during the > 9000 patients with ACS from one of the participating first month of follow-up. Another study that used claims data centers in this current study (43.7%) [11]. Additionally, a from Dutch health insurance companies observed guideline- similar pattern of increased OMT at 1 month and decreased recommended OMT prescription rates of 49% during the OMT at 12 months was observed, but OMT at 1 month first 12 months after ACS [12]. However, that study only (60.1%) in the current study was higher than the 46.6% in the single-center study. This study was conducted in two Percentage Percentage Percentage Percentage 226 N. P. G. Hoedemaker et al. Aspirin P2Y12 inhibitor 100 100 75 75 50 50 25 25 0 0 Discharge 1 month 6 months12 months Discharge 1 month 6 months 12 months Statin Beta−blocker 100 100 75 75 50 50 25 25 0 0 Discharge 1 month 6 months12 months Discharge 1 month 6 months 12 months ACEi/ARB OAC 100 100 75 75 50 50 25 25 0 0 Discharge 1 month 6 months12 months Discharge 1 month 6 months 12 months PPI Age <4545−54 55−6465−74 75−84>84 Discharge 1 month 6 months12 months Fig. 3 Optimal medical therapy prescription at discharge, 1, 6, and 12 months stratified by age. ACEi/ARB angiotensin-converting enzyme inhib- itor, ARB angiotensin-receptor blocker, OAC oral anticoagulants, OMT optimal medical therapy, PPI proton pump inhibitors counted fulfilled pharmacy prescriptions, which could reduced bleeding [15, 16]. However, the GLOBAL LEAD- explain the lower percentage of OMT use. ERS trial failed to show a benefit from ticagrelor monother - apy in patients with ACS [17]. The majority of patients with 4.2 Antiplatelet Therapy an indication for a PPI (i.e., DAPT, NOAC, age ≥ 65 years) were treated in accordance with ESC recommendations [5]. We observed DAPT durations of at least 12 months in Remarkably, CABG during hospitalization was an inde- approximately 50% of patients, with 33% stopping DAPT pendent negative predictor of OMT prescription at discharge between 6 and 12 months. This indicates that a substantial and 12 months. This was most likely because of a signifi- group of patients terminated DAPT before 6 months. There cantly lower rate of P2Y12 inhibitor use among patients who may be several explanations for this. A shorter DAPT dura- underwent CABG. A recent Swiss study observed similar tion is recommended for patients with high bleeding risk [3, results, and these may be explained by clinicians’ reluctance 4]. Moreover, patients with an indication for NOACs (≤ 20% to reinitiate DAPT after cardiac surgery [18]. in our study) may use triple therapy with DAPT for only 1–6 months and thereafter continue on dual therapy alone [5]. 4.3 OMT in Left Ventricular Ejection Fraction ≤ 40% Recently, the AUGUSTUS and RE-DUAL PCI trials demon- strated that a NOAC in addition to a P2Y12 inhibitor could We observed numerically higher rates of OMT in patients be an additional treatment option in patients with ACS with with a reduced LVEF compared with those with preserved atrial fibrillation who underwent PCI [13, 14]. Furthermore, LVEF, a finding that was in accordance with ESC guide- approximately 5% of patients switched from prasugrel or lines. At 6 and 12 months, β-blocker prescriptions decreased ticagrelor to clopidogrel. The TROPICAL-ACS and TOPIC in patients with preserved LVEF. National registry stud- studies demonstrated that switching from a novel P2Y12 ies have challenged the usefulness of long-term β-blocker inhibitor to clopidogrel was safe for ischemic endpoints and treatment in patients with ACS with preserved LVEF Percentage Optimal Medical Therapy After Acute Coronary Syndrome 227 in the PCI era [19, 20]. Five ongoing randomized trials per guidelines. The incidence of bleeding and dyspnea as a (AβYSS, NCT03498066; BETAMI, NCT03646357; DAN- reason for discontinuation of P2Y12 inhibitors corresponds BLOCK, NCT03778554; REBOOT-CNIC, NCT03596385; with results from another Dutch registry [31]. ACEi/ARBs REDUCE-SWEDEHEART, NCT03278509) are studying were stopped in 27% and 20%, respectively. Although not the effect of β-blocker withdrawal on hard clinical endpoints all reasons for withdrawal were known, the rate of ACEi in patients with ACS. Our study showed that discharge discontinuation because of cough (3.3%) was comparable ACEi/ARB prescriptions in patients with a class IA indica- with that in other reports (4.2–5.1%) [32, 33]. Statin-related tion were 63.7% in patients with STEMI and 72.1% in those myalgia or myopathy was the most reported side effect with NSTEMI, which later increased to 86.7 and 79.3% at 1 (4.5%). The discontinuation rate in our study was lower than month, respectively. Room for improvement of ACEi/ARB in randomized and observational studies, ranging from 8.8 treatment during the first month may still exist since most of to 12.0% [34–36]. However, statin users in these studies had their benefit is observed during the first week [21]. both primary and secondary prevention indications. Possi- bly, muscle-related statin discontinuation is lower in second- 4.4 Subgroups ary than in primary prevention because patients who have experienced a cardiovascular event are more willing to per- While OMT prescription at discharge did not differ between sist with (less intensive) statins, despite muscle symptoms. STEMI and NSTEMI, it was lower in patients with NSTEMI at 1 and 6 months. In particular, antiplatelet and statin ther-4.6 Limitations apy rates were lower in patients with NSTEMI. Patients with NSTEMI more often had a higher risk profile that included Several limitations of this study should be addressed. First, diabetes mellitus and previous cardiovascular events, indi- this was an observational study in two PCI centers and may cating a risk–treatment paradox that has been previously not reflect practice elsewhere. Second, the limited sample reported in patients with NSTEMI [22, 23]. size and missing data for several baseline characteristics pre- Additionally, OMT prescription was lower among vented us from analyzing a relation between OMT and out- women, which was also observed in other studies [24, 25]. come. We were only able to obtain mortality data through the Our results showed this difference was caused by lower Dutch national population registry and were unable to report P2Y12 inhibitor and statin use in women. In the PLATO other important clinical outcomes such as cause of death, trial, female sex was independently associated with major recurrent MI, or revascularization. Third, during follow-up, bleeding [26]. This could explain the difference in P2Y12 the number of patients with known medication decreased, inhibitor use at discharge and 1 month. It has been reported which could be a potential cause of bias. Fourth, the date of that women stopped a statin more often than men because of P2Y12 inhibitor cessation was not available, and we only side effects associated with statins, but women also received collected DAPT prescription data at 1, 6, and 12 months post- less information related to their cardiovascular risk profile discharge. Therefore, we could not calculate the exact DAPT and so may have been unaware of the importance of statin duration and were unable to determine the number of patients therapy [27]. who completed almost 12 months of DAPT (i.e., 335–364 Likewise, the decreasing trend in OMT prescription that days). Finally, we did not account for multiple testing. was observed in the elderly could also be explained by a decrease in antiplatelet therapy and statins. Age is an impor- tant risk factor, and short-term DAPT may be more benefi-5 Conclusions cial in elderly patients [28]. Although the benefits of statin therapy in elderly patients are clear, the treatment–benefit In this pilot study that aimed to extend the national Dutch ratio of statins should be evaluated according to patients’ ACS registry to patients with STEMI and NSTEMI, OMT life expectancy [29]. Nevertheless, in the current aging ACS prescription was comparable to other local registries and was population, it remains important to know that OMT prescrip- lower in women and patients with NSTEMI and decreased tion is associated with a survival benefit in all ages [30]. with age. Acknowledgements The authors thank Ruben de Winter, Shahla 4.5 Discontinuation Ajoebi, and Wesley van den Busken for their assistance with the devel- opment of the registry database. We assessed drug discontinuation in one of the participat- Declarations ing centers that recorded reasons for withdrawal and found discontinuation was highest for P2Y12 inhibitors and ACEi/ Funding This study was funded by an unrestricted research grant from ARBs. As expected, P2Y12 inhibitors were mostly stopped AstraZeneca Netherlands B.V. because DAPT, triple, or dual therapy treatment ended as 228 N. P. G. Hoedemaker et al. Conflict of interest P. Damman has received an unrestricted research The Task Force for dual antiplatelet therapy in coronary artery grant from AstraZeneca Netherlands B.V. Niels PG Hoedemaker, Rob- disease of the European Society of Cardiology (ESC) and of the bert J de Winter, Arnoud van ’t Hof, and Evelien Kolkman have no European Association for Cardio-Thoracic Surgery (EACTS). Eur potential conflicts of interest that might be relevant to the contents of Heart J. 2018;39(3):213–60. this manuscript. 6. Ozcan C, Juel K, Flensted Lassen J, von Kappelgaard LM, Mortensen PE, Gislason G. The Danish Heart Registry. Clin Epi- Ethics approval This study was conducted with a waiver from the med- demiol. 2016;8:503–8. ical ethical committee of the Academic Medical Center in Amsterdam. 7. Jernberg T, Attebring MF, Hambraeus K, Ivert T, James S, Jepps- According to Dutch law applicable at the time of the study period, son A, et  al. The Swedish Web-system for enhancement and written informed consent for the conduction of this registry study was development of evidence-based care in heart disease evaluated not required. according to recommended therapies (SWEDEHEART). Heart. 2010;96(20):1617–21. Consent to participate Not applicable. 8. Bebb O, Hall M, Fox KAA, Dondo TB, Timmis A, Bueno H, et al. Performance of hospitals according to the ESC ACCA qual- Consent for publication Not applicable. ity indicators and 30-day mortality for acute myocardial infarc- tion: national cohort study using the United Kingdom Myocardial Availability of data and material Not applicable. Ischaemia National Audit Project (MINAP) register. Eur Heart J. 2017;38(13):974–82. Code availability Not applicable. 9. Hoedemaker NP, Ten Haaf ME, Maas JC, Damman P, Appelman Y, Tijssen JG, et al. Practice of ST-segment elevation myocardial infarction care in the Netherlands during four snapshot weeks with Open Access This article is licensed under a Creative Commons Attri- the National Cardiovascular Database Registry for Acute Coro- bution-NonCommercial 4.0 International License, which permits any nary Syndrome. Neth Heart J. 2017;25(4):264–70. non-commercial use, sharing, adaptation, distribution and reproduction 10. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, in any medium or format, as long as you give appropriate credit to the White HD, et al. Third universal definition of myocardial infarc- original author(s) and the source, provide a link to the Creative Com- tion. Eur Heart J. 2012;33(20):2551–67. mons licence, and indicate if changes were made. The images or other 11. Hoedemaker NPG, Damman P, Ottervanger JP, Dambrink JHE, third party material in this article are included in the article’s Creative Gosselink ATM, Kedhi E, et al. Trends in optimal medical therapy Commons licence, unless indicated otherwise in a credit line to the prescription and mortality after admission for acute coronary syn- material. If material is not included in the article’s Creative Commons drome: a 9-year experience in a real-world setting. 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Optimal Medical Therapy Prescription in Patients with Acute Coronary Syndrome in the Netherlands: A Multicenter Pilot Registry

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Springer Journals
Copyright
Copyright © The Author(s) 2020
ISSN
1175-3277
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1179-187X
DOI
10.1007/s40256-020-00427-9
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Abstract

Background Unlike neighboring countries, the Netherlands does not have a national acute coronary syndrome (ACS) registry to evaluate quality of care. Objective We conducted a pilot registry in two hospitals to assess the prescription of guideline-recommended therapies in Dutch patients with ACS. Methods We included all consecutive patients with ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) (n = 1309) admitted to two Dutch percutaneous coronary intervention centers between March 2015 and February 2016. We collected follow-up medication use and reasons for discontinuation at discharge and 1, 6, and 12 months post-discharge. We assessed the use of optimal medical therapy (OMT), defined as the combined prescription of aspirin, P2Y12 inhibitors, statins, β-blockers, and angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. Results OMT prescription was 43.2% at discharge, 60.1% at 1 month, and 28.7% at 12 months. At 1 month, OMT prescrip- tion was significantly lower in patients with NSTEMI (51.8 vs. 65.7% for STEMI; p < 0.001). OMT prescription was lower in women (6 months: 55.4 vs. 62.0%, p = 0.036) and in elderly patients. Conclusion In this pilot study that aimed to extend a national Dutch ACS registry to patients with STEMI and NSTEMI, OMT prescription was comparable to that in other local registries, was lower in women and patients with NSTEMI, and decreased with increasing age. 1 Introduction and those with non-ST-segment elevation myocardial infarc- tion (NSTEMI) [1, 2]. During the last two decades, the development of invasive and Guideline-recommended therapies in patients with acute medical therapies has improved outcomes in both patients coronary syndrome (ACS) include invasive treatments such with ST-segment elevation myocardial infarction (STEMI) as coronary angiography with subsequent percutaneous cor- onary intervention (PCI) or coronary artery bypass grafting Electronic supplementary material The online version of this (CABG) and optimal medical therapy (OMT) [3, 4]. OMT article (https ://doi.org/10.1007/s4025 6-020-00427 -9) contains consists of aspirin, P2Y12 inhibitor, statin, β-blocker, and an supplementary material, which is available to authorized users. angiotensin-converting enzyme inhibitor (ACEi) or angio- * Niels P. G. Hoedemaker tensin-receptor blocker (ARB). β-blockers and ACEi/ARBs n.p.g.hoedemaker@olvg.nl have a class IA recommendation in patients with ACS with a reduced left ventricular ejection fraction (LVEF ≤ 40%) [3, Heart Center, Department of Cardiology, Amsterdam 4]. Dual therapy with a P2Y12 inhibitor and a coumarin or Cardiovascular Sciences, Amsterdam UMC, Location AMC, University of Amsterdam, Meibergdreef 9, novel oral anticoagulant (NOAC) as a replacement for aspi- 1105 AZ Amsterdam, The Netherlands rin is also considered OMT. Additionally, prescription of a Department of Cardiology, Maastricht University Medical proton pump inhibitor (PPI) is recommended in patients with Center, Maastricht, The Netherlands ACS aged ≥ 65 years receiving dual antiplatelet therapy Diagram B.V, Zwolle, The Netherlands (DAPT) and NOACs [5]. National registries in Denmark, Sweden, and the UK Department of Cardiology, Isala Klinieken, Zwolle, The Netherlands have contributed to improve adherence to the abovemen- tioned guideline-recommended therapies, which has been Department of Cardiology, Radboud University Medical Center, Nijmegen, The Netherlands linked to an overall benefit for patients with ACS [6 –8]. Vol.:(0123456789) 220 N. P. G. Hoedemaker et al. until 29 February 2016. Patients were diagnosed if they had KeyPoints ischemic symptoms lasting > 20 min and elevated cardiac biomarkers and/or new ST-segment elevation in two contigu- Guideline-recommended optimal medical therapy ous leads, left bundle branch block, ST-T or T-wave changes, (OMT) for secondary prevention after acute coronary or Q-waves on a 12-lead electrocardiogram. Only patients syndrome (ACS) consists of aspirin, P2Y12 inhibitors, with type 1 myocardial infarction (MI) according to the statins, β-blockers, and angiotensin-converting enzyme Third Universal Definition of MI were included [10]. Any inhibitors or angiotensin-receptor blockers. discrepancies on the assessment of MI type were discussed until consensus was reached. Most European countries have a national ACS registry, which has contributed to improving adherence to OMT; 2.3 Treatment however, the Netherlands does not have a national ACS registry. The preferred treatment strategy in patients with STEMI In this multicenter pilot registry of two Dutch hospitals, was primary PCI. In patients with NSTEMI, the timing and OMT use was significantly lower among patients with performance of angiography and revascularization were in non-ST-elevation myocardial infarction, women, and accordance with the European guidelines [3, 4]. Patients elderly patients. undergoing angiography were pretreated with aspirin, hepa- rin, and a P2Y12 inhibitor (ticagrelor 180 mg or clopidogrel Similar findings were observed in other registry studies, 600 mg loading dose). CABG was performed if indicated. so further efforts to improve OMT use should focus on Prescription of guideline-recommended therapies and refer- these subgroups. ral to cardiac rehabilitation was in accordance with the 2012 STEMI and 2015 NSTE-ACS guidelines from the European However, the Netherlands does not have a national ACS Society of Cardiology (ESC) and was encouraged in all registry. A report by the National Cardiovascular Database patients [3, 4]. Registry (NCDR) demonstrated the feasibility of a Dutch ACS registry but only enrolled patients with STEMI over a 2.4 Data Collection and Follow‑Up 4-week period [9]. The current study is a pilot study from two Dutch PCI centers that aimed to expand the NCDR reg- Data were prospectively recorded in a dedicated case report istry by including both patients with STEMI and those with form using an anonymized patient identification number. NSTEMI over a full year of enrollment. We assessed the Variables included demographics, risk factors, medical his- prescription of guideline-recommended medical therapies tory, procedural characteristics, LVEF measured by echocar- and reasons for drug discontinuation after ACS. diography, and medication prescription at discharge and 1, 6, and 12 months post-discharge. We collected follow-up data on medication prescription and (at one center) discontinu- 2 Methods ation from hospital records and/or via telephone interviews with a trained research physician at 1, 6, and 12 months. 2.1 Study Setting and Design We obtained vital status from the Dutch national population registry. The two datasets were collected and merged for This study combines ACS registries from two PCI centers analysis at the AMC in Amsterdam. This study was con- in the Netherlands: the Academic Medical Centre (AMC) ducted with a waiver from the medical ethical committee of in Amsterdam and Isala Hospital Zwolle. Both centers the AMC in Amsterdam. According to Dutch law applicable recorded their own separate prospective observational reg- at the time of the study period, written informed consent for istries, based on the variable set of the NCDR, the predeces- the conduct of this registry study was not required. sors of the current Netherlands Heart Registry (NHR). The NHR was established in 2017, 1 year after the enrollment of 2.5 Definitions and Outcomes this study was completed. Representatives from both centers agreed to combine the two registries with the aim to assess The main outcome of this study was OMT at discharge and medication prescription. during follow-up. OMT was defined as a combination of aspirin, P2Y12 inhibitor, statin, β-blocker, and ACEi/ARB. 2.2 Patients Prescription of dual therapy (P2Y12 inhibitor with a NOAC) with a statin, β-blocker, and ACEi/ARB was also regarded We enrolled all consecutive patients with STEMI or as OMT. We assessed OMT prescription stratified by ACS NSTEMI admitted to our hospitals from 1 March 2015 type (STEMI vs. NSTEMI), sex, and age. We also evaluated Optimal Medical Therapy After Acute Coronary Syndrome 221 OMT, β-blocker, and ACEi/ARB prescription in patients coronary angiography (94.9%), and 81.8% of the patients with a preserved (> 40%) or reduced (≤ 40%) LVEF. Fur- were treated with PCI. PCI performance was significantly thermore, we evaluated prescriptions among patients with higher among patients with STEMI than those with NSTEMI a class IA indication for ACEi/ARBs and in patients with (90.7 vs. 62.8%; p < 0.001). CABG was performed in 7.3% STEMI (LVEF ≤ 40%, hypertension, diabetes mellitus, ante- of patients. rior MI) or NSTEMI (LVEF ≤ 40%, hypertension, diabetes mellitus) [3, 4]. We assessed the duration of DAPT prescrip-3.2 Mortality Outcome tion follow-up and switching between novel P2Y12 inhibi- tors (ticagrelor or prasugrel) and clopidogrel. Finally, we Vital status from the Dutch national population registry at 1 evaluated PPI prescriptions among patients receiving DAPT year was obtained for 1300 patients (99.3%). Nine patients or a NOAC and aged ≥ 65 years [5]. were not registered as inhabitants of the Netherlands so their vital status could not be obtained. In-hospital mortality was 2.6 Statistical Analysis 3.7%, 30-day mortality 4.5%, and 1-year mortality 7.4%. Continuous variables are presented as mean and standard 3.3 Medication at Discharge and During Follow‑Up deviation or as median and interquartile range (IQR) for nor- mal and skewed distributions, respectively. All categorical A flow chart of patients recruited and lost to medication variables are presented as absolute frequencies and percent- follow-up is provided in the Electronic Supplementary Mate- ages. Differences between groups were evaluated using the rial (ESM; Tables 4 and 5). Prescription of medication cat- unpaired t test or Mann–Whitney test (nonparametric) for egories is displayed in Table 2. Prescription at discharge continuous variables and the χ test for categorical variables. was highest for aspirin (88.8%), statins (86.6%), and P2Y12 The linear-by-linear association test was used to evaluate dif- inhibitors (84.8%). Prescription rates increased at 1 month ferences between age groups. We identified variables asso- but decreased at 6 and 12 months. Combined prescription of ciated with OMT prescription at discharge and 12-month medication is presented in Table 3. OMT prescription at dis- follow-up based on differences in baseline characteristics charge was 43.2%, increased to 60.1% at 1 month, and was and variables of interest according to guideline recommen- 50.8% and 28.7% at 6 and 12 months, respectively. Patients dations. We calculated odds ratios (ORs) and adjusted ORs not receiving OMT at discharge had a significantly shorter based on univariate and multivariate logistic regression admission length than did those receiving OMT (1.0 days models, respectively. All variables identified (age ≥65 years, [IQR 0.0–5.0] vs. 3.0 [IQR 1.0–5.0]; p < 0.001). OMT pre- female sex, hypertension, diabetes mellitus, hypercholester- scription at discharge and 1 and 6 months was higher among olemia, chronic kidney disease [creatinine clearance ≤ 50 patients with a reduced ejection fraction, but this was not ml/min], previous MI, previous CABG, previous stroke, statistically significant (Fig.  1a). STEMI, PCI performance, and CABG performance) were used in the multivariate model. A p value of < 0.05 (two-3.4 Antiplatelet Therapy sided) was considered statistically significant. All analyses were performed using SPSS version 25.0. Ticagrelor was the most prescribed P2Y12 inhibitor, with 58.9% of patients receiving it at discharge, whereas 25.3% of the patients received clopidogrel and < 1% received prasu- 3 Results grel. At discharge, 79.9% of patients received DAPT and 4.0% received dual therapy (NOAC and P2Y12 inhibitor). Between March 2015 and February 2016, a total of 1309 This decreased to 43.0% DAPT and 7.0% dual therapy at patients with ACS were included in the registry: 528 (40.3%) 12 months. Complete 12-month follow-up on DAPT pre- from the Amsterdam registry and 781 (59.7%) from the scription was available in 715 patients (54.6%). In total, 52 Zwolle registry. patients (7.3%) stopped using DAPT between discharge and 1 month, 12.9% stopped between 1 and 6 months, and 33.0% 3.1 Baseline and Procedural Characteristics stopped between 6 and 12 months. Approximately half of the patients (46.9%) received DAPT for at least 12 months. Table 1 displays the baseline and procedural characteristics. From discharge until 1 month, 28 patients (3.6%) switched The mean age was 64.9 years, and 28.6% of the patients were from a novel P2Y12 inhibitor to clopidogrel, and 14 patients women (Table 1). Hypertension was present in 45.6%, and (1.8%) switched to a novel P2Y12 inhibitor. Between 1 and 17.2% had diabetes mellitus. Approximately two-thirds of 6 months, 36 patients (4.5%) switched to clopidogrel, and patients were admitted with STEMI (64.6%) and one-third nine patients (1.1%) switched to a novel P2Y12 inhibitor. with NSTEMI (35.4%). The majority of patients underwent Between 6 and 12 months, 23 patients (2.4%) switched 222 N. P. G. Hoedemaker et al. from a novel P2Y12 inhibitor to clopidogrel, and three Table 1 Baseline characteristics patients (0.3%) switched from clopidogrel to a novel P2Y12 Characteristics Overall (n = 1309) inhibitor. Demographics Age, years 64.9 ± 12.7 3.5 β‑Blockers, Angiotensin‑Converting Enzyme Women 374/1309 (28.6) Inhibitors, and Angiotensin‑Receptor Blockers Risk factors According to Ejection Fraction Hypertension 578/1268 (45.6) Diabetes mellitus 218/1270 (17.2) β-blocker prescription at discharge was similar for patients  Smoking status with preserved or reduced LVEF (82.4 vs. 81.1%; p = Current 435/1238 (35.1) 0.763). At 1, 6, and 12 months, β-blocker rates were higher Past smoker 170/1238 (13.7) among patients with reduced LVEF. ACEi/ARB prescription Never smoked 461/1238 (37.2) was markedly higher among patients with reduced LVEF. At Unknown 172/1238 (13.9) discharge, 63.7% of the patients with STEMI with a class IA Hypercholesterolemia 338/1255 (26.9) indication for ACEi/ARBs were treated according to ESC Family history of CVD 420/1156 (36.3) guidelines. This rate increased to 86.7%, 83.8%, and 81.9% Medical history at 1-, 6-, and 12-month follow-up, respectively. Among COPD 87/1054 (8.3) patients with NSTEMI with a class IA indication for ACEi/ Chronic kidney disease 105/1093 (9.6) ARBs, 72.4% were prescribed one of these drugs in accord- Previous MI 108/1093 (8.3) ance with the guidelines. This later increased to 79.3% at 1 Previous PCI 131/1309 (10.0) month, 75.5% at 6 months, and 74.7% at 12 months. Co-pre- Previous CABG 51/1309 (3.9) scription of a β-blocker and an ACEi/ARB in patients with Previous stroke 63/1063 (5.9) reduced LVEF was 62.1% at discharge, 77.5% at 1 month, Clinical presentation 71.8% at 6 months, and 70.0% at 12 months. Additional STEMI 845/1309 (64.6) results on combined prescriptions according to LVEF are NSTEMI 464/1309 (35.4) presented in Tables 2 and 3 in the ESM. Killip class > 2 60/436 (13.8) Cardiogenic shock 58/1309 (4.4) 3.6 Proton Pump Inhibitors OHCA 74/1309 (5.7) Invasive treatment during admission Among patients receiving DAPT, PPI prescription was Coronary angiography 1242/1309 (94.9) 73.7% and approximately 85% during follow-up (1 month, PCI 978/1195 (81.8) 86.4%; 6 months, 84.5%; and 12 months, 86.2%). PPI pre- Stent type scription was even higher for patients receiving NOACs: DES 784/853 (91.9) 84.1% at discharge and 91.4%, 89.0%, and 91.6% at 1, 6, and BMS 14/853 (1.6) 12 months, respectively. A PPI was prescribed in 79.3% of BVS 55/853 (6.4) patients aged ≥ 65 years at discharge and in 93.2%, 90.5%, CABG 87/1195 (7.3) and 89.5% at 1, 6, and 12-month follow-up. LVEF during admission Preserved (> 40%) 320/430 (74.4) 3.7 STEMI vs. NSTEMI Reduced (≤ 40%) 110/430 (25.6) Length of stay, days 2.0 (1.0–5.0) OMT at discharge was no different between patients with STEMI or NSTEMI (43.9 vs. 41.9%; p = 0.524; Fig. 1b). Data are presented as mean ± standard deviation, N (%), or median OMT prescription was significantly higher among patients (interquartile range) unless otherwise indicated with STEMI at 1 and 6 months (65.7 vs. 51.8%, p < 0.001 BMS bare metal stent, BVS bioresorbable scaffold, CABG coronary and 54.2 vs. 46.0%, p = 0.017, respectively). This difference artery bypass grafting, COPD chronic obstructive pulmonary dis- ease, CVD cardiovascular disease, DES drug-eluting stent, LVEF left was mainly because of higher rates of P2Y12 inhibitors and ventricular ejection fraction, MI myocardial infarction, NSTEMI non- ACEi/ARBs among patients with STEMI (Tables 4 and 5 in ST-segment elevation myocardial infarction, OHCA out-of-hospital the ESM). There were no differences in OMT at 12 months cardiac arrest, PCI percutaneous coronary intervention, STEMI ST- (28.5 vs. 29.0%, p = 0.891). segment elevation myocardial infarction Optimal Medical Therapy After Acute Coronary Syndrome 223 Table 2 Medication at discharge 1, 6, and 12 months after acute coronary syndrome Timepoint Medication Overall (n = 1309) LVEF > 40% (n = 320) LVEF ≤ 40% (n = 110) p value Discharge Aspirin 986/1110 (88.8) P2Y12 inhibitor 941/1110 (84.8) Statin 958/1110 (86.3) β-blocker 860/1110 (77.5) 253/307 (82.4) 77/95 (81.1) 0.763 ACE inhibitor/ARB 676/1110 (60.9) 187/307 (60.9) 64/95 (67.4) 0.256 NOAC 164/1110 (14.8) PPI 806/1110 (72.6) 1 month Aspirin 870/961 (90.5) P2Y12 inhibitor 843/961 (87.7) Statin 897/960 (93.4) β-blocker 850/959 (88.6) 240/270 (88.9) 74/80 (92.5) 0.350 ACE inhibitor/ARB 750/957 (78.4) 194/270 (71.9) 66/80 (82.5) 0.056 NOAC 191/961 (19.9) PPI 804/934 (86.1) 6 months Aspirin 765/893 (85.7) P2Y12 inhibitor 726/893 (81.3) Statin 799/892 (89.6) β-blocker 738/890 (82.9) 216/266 (81.2) 66/71 (93.0) 0.017 ACE inhibitor/ARB 668/890 (75.1) 193/266 (72.6) 56/71 (78.9) 0.282 OAC 172/892 (19.3) PPI 745/889 (83.8) 12 months Aspirin 729/877 (83.1) P2Y12 inhibitor 452/876 (51.6) Statin 768/878 (87.5) β-blocker 675/876 (77.1) 209/264 (79.2) 60/70 (85.7) 0.219 ACE inhibitor/ARB 637/875 (72.8) 180/264 (68.2) 58/70 (82.9) 0.016 OAC 155/877 (17.7) PPI 714/875 (81.6) Data are presented as N (%) unless otherwise indicated ACE angiotensin-converting enzyme, ARB angiotensin-receptor blocker, LVEF left ventricular ejection fraction, NOAC novel oral anticoagula- tion, PPI proton pump inhibitor and PPI prescriptions increased with age (Tables 8 and 9 in 3.8 Sex Differences the ESM). Women had lower OMT prescription rates at discharge (45.9 3.10 Predictors of Optimal Medical Therapy (OMT) vs. 36.6%; p = 0.005) and during follow-up, but this was only significantly different at 6 months (62.0 vs. 55.4%; p = We performed univariate and multivariate logistic regres- 0.036; Fig. 1c). The differences can be explained by lower sion to identify predictors of OMT prescription at discharge rates of P2Y12 inhibitor and statin prescriptions among and 12-month follow-up (Table 10 in the ESM). Univariate women (Tables 6 and 7 in the ESM). predictors of OMT prescription at discharge were female sex and undergoing PCI or CABG. After multivariate adjust- 3.9 Age ment, female sex (OR 0.64; p = 0.007) and undergoing CABG (OR 0.35; p = 0.003) remained associated with OMT In general, OMT prescription decreased with age, both at prescription at discharge. Univariate predictors of OMT pre- discharge and during follow-up (Fig.  2). This decreasing scription at 12 months were female sex, previous stroke, and trend was significant at 1-month follow-up (p = 0.001). undergoing CABG. However, after multivariate adjustment, Figure  3 displays prescription rates for individual OMT only undergoing CABG remained independently associated medications according to age. The use of aspirin, P2Y12 with OMT prescription at discharge (OR 0.25; p = 0.007). inhibitors, and statins decreased with age, whereas NOAC 224 N. P. G. Hoedemaker et al. Table 3 Medication combinations at discharge and 1, 6, and 12 month after acute coronary syndrome Timepoint Medication Overall (n = 1309) LVEF > 40% (n = 320) LVEF ≤ 40% (n = 110) p value Discharge DAPT or dual therapy 929/1110 (83.7) DAPT 885/1110 (79.7) Dual therapy 44/1110 (4.0) DAPT or dual therapy and statin 842/1110 (75.9) DAPT and statin 807/1110 (72.7) Dual therapy and statin 35/1110 (3.2) OMT 479/1110 (43.2) 145/307 (47.2) 53/95 (55.8) 0.145 OMT with aspirin 458/1110 (41.3) 138/307 (45.0) 48/95 (50.5) 0.341 OMT with NOAC 21/1110 (1.9) 7/307 (2.3) 5/95 (5.3) 0.135 1 month DAPT or dual therapy 837/961 (87.1) DAPT 782/961 (81.4) Dual therapy 55/961 (5.7) DAPT or dual therapy and statin 790/960 (82.3) DAPT and statin 741/960 (77.2) Dual therapy and statin 49/960 (5.1) OMT 575/956 (60.1) 159/270 (58.9) 50/80 (62.5) 0.563 OMT with aspirin 540/956 (56.5) 150/270 (55.6) 44/50 (55.0) 0.930 OMT with NOAC 35/956 (3.7) 9/270 (3.3) 6/80 (7.5) 0.106 6 months DAPT or dual therapy 717/892 (80.4) DAPT 637/893 (71.3) Dual therapy 80/892 (9.0) DAPT or dual therapy and statin 651/891 (73.1) DAPT and statin 580/892 (65.0) Dual therapy and statin 71/891 (8.0) OMT 452/889 (50.8) 137/266 (51.5) 41/71 (57.7) 0.349 OMT with aspirin 394/889 (44.3) 113/266 (42.5) 33/71 (46.5) 0.546 OMT with NOAC 58/889 (6.5) 24/266 (9.0) 8/71 (11.3) 0.566 12 months DAPT or dual therapy 438/876 (50.0) DAPT 377/876 (43.0) Dual therapy 61/876 (7.0) DAPT or dual therapy and statin 391/876 (44.6) DAPT and statin 336/876 (38.4) Dual therapy and statin 55/876 (6.3) OMT 251/874 (28.7) 84/264 (31.8) 24/70 (34.3) 0.695 OMT with aspirin 209/874 (23.9) 65/264 (24.6) 20/70 (28.6) 0.500 OMT with NOAC 42/874 (4.8) 19/264 (7.2) 4/70 (5.7) 0.663 DAPT dual antiplatelet therapy, LVEF left ventricular ejection fraction, NOAC novel oral anticoagulation, OMT optimal medical therapy With regard to this result, we identified that P2Y12 inhibi- follows. First, 43.2%, of patients were discharged with OMT, tor use (37 vs. 89.5% at discharge and 25.4 vs. 54.1%) was which increased to 60.1% at 1 month and decreased to 28.7% significantly lower among patients who underwent CABG. at 12 months. Second, OMT prescription was numerically higher among patients with reduced LVEF, but this differ - ence was not statistically significant. Third, OMT prescrip- 4 Discussion tion was lower in patients with NSTEMI (at 1 and 6 months) and in women. Fourth, there was a decreasing trend in OMT In this study, we report adherence to guidelines in OMT prescription with increasing age. Finally, discontinuation prescriptions in consecutive patients with ACS from two PCI was highest for P2Y12 inhibitors (as per guidelines) and centers in the Netherlands. Our results can be summarized as ACEi/ARBs. Optimal Medical Therapy After Acute Coronary Syndrome 225 LVEF ACS Gender AB C 80 80 80 Preserved STEMI Men p=0.563 Reduced p<0.001 NSTEMI p=0.060 Women 70 p=0.349 70 p=0.017 70 p=0.036 65.7 p=0.145 62.5 p=0.524 p=0.005 62.0 58.9 60 57.7 60 60 55.8 55.4 54.2 53.1 51.5 51.8 50 47.2 50 50 46.0 45.9 45.3 43.9 p=0.695 p=0.891 p=0.281 41.9 40 40 40 36.6 34.3 31.8 29.8 29.0 28.5 30 30 30 26.1 20 20 20 10 10 10 0 0 0 Discharge1 month6 months 12 months Discharge1 month6 months 12 months Discharge 1 month6 months 12 months OMT prescription Fig. 1 Optimal medical therapy prescription at discharge, 1, 6, and 12 scription in patients with ACS with ST-elevation myocardial infarc- months in different subgroups. a optimal medical therapy (OMT) in tion (STEMI) or non-ST-segment elevation myocardial infarction patients with acute coronary syndrome (ACS) with a preserved ver- (NSTEMI). c displays differences in OMT prescription between men sus a reduced left ventricular ejection fraction (LVEF). b OMT pre- and women Fig. 2 Optimal medical therapy Age prescription at discharge, 1, 6, <45 and 12 months stratified by age. p=0.001 45−54 OMT optimal medical therapy 55−64 65−74 75−84 >84 60 p=0.086 p=0.230 40 p=0.646 Discharge 1 month6 months12 months OMT prescription PCI centers where early discharge and transfer back to the 4.1 Context and Interpretation referring regional non-PCI centers is common. This could explain why the median length of stay for patients without The discharge OMT prescription rate in our study (43.2%) OMT at discharge was 2 days shorter than those with OMT corresponds with that in a single-center registry study with and account for the observed increase in OMT during the > 9000 patients with ACS from one of the participating first month of follow-up. Another study that used claims data centers in this current study (43.7%) [11]. Additionally, a from Dutch health insurance companies observed guideline- similar pattern of increased OMT at 1 month and decreased recommended OMT prescription rates of 49% during the OMT at 12 months was observed, but OMT at 1 month first 12 months after ACS [12]. However, that study only (60.1%) in the current study was higher than the 46.6% in the single-center study. This study was conducted in two Percentage Percentage Percentage Percentage 226 N. P. G. Hoedemaker et al. Aspirin P2Y12 inhibitor 100 100 75 75 50 50 25 25 0 0 Discharge 1 month 6 months12 months Discharge 1 month 6 months 12 months Statin Beta−blocker 100 100 75 75 50 50 25 25 0 0 Discharge 1 month 6 months12 months Discharge 1 month 6 months 12 months ACEi/ARB OAC 100 100 75 75 50 50 25 25 0 0 Discharge 1 month 6 months12 months Discharge 1 month 6 months 12 months PPI Age <4545−54 55−6465−74 75−84>84 Discharge 1 month 6 months12 months Fig. 3 Optimal medical therapy prescription at discharge, 1, 6, and 12 months stratified by age. ACEi/ARB angiotensin-converting enzyme inhib- itor, ARB angiotensin-receptor blocker, OAC oral anticoagulants, OMT optimal medical therapy, PPI proton pump inhibitors counted fulfilled pharmacy prescriptions, which could reduced bleeding [15, 16]. However, the GLOBAL LEAD- explain the lower percentage of OMT use. ERS trial failed to show a benefit from ticagrelor monother - apy in patients with ACS [17]. The majority of patients with 4.2 Antiplatelet Therapy an indication for a PPI (i.e., DAPT, NOAC, age ≥ 65 years) were treated in accordance with ESC recommendations [5]. We observed DAPT durations of at least 12 months in Remarkably, CABG during hospitalization was an inde- approximately 50% of patients, with 33% stopping DAPT pendent negative predictor of OMT prescription at discharge between 6 and 12 months. This indicates that a substantial and 12 months. This was most likely because of a signifi- group of patients terminated DAPT before 6 months. There cantly lower rate of P2Y12 inhibitor use among patients who may be several explanations for this. A shorter DAPT dura- underwent CABG. A recent Swiss study observed similar tion is recommended for patients with high bleeding risk [3, results, and these may be explained by clinicians’ reluctance 4]. Moreover, patients with an indication for NOACs (≤ 20% to reinitiate DAPT after cardiac surgery [18]. in our study) may use triple therapy with DAPT for only 1–6 months and thereafter continue on dual therapy alone [5]. 4.3 OMT in Left Ventricular Ejection Fraction ≤ 40% Recently, the AUGUSTUS and RE-DUAL PCI trials demon- strated that a NOAC in addition to a P2Y12 inhibitor could We observed numerically higher rates of OMT in patients be an additional treatment option in patients with ACS with with a reduced LVEF compared with those with preserved atrial fibrillation who underwent PCI [13, 14]. Furthermore, LVEF, a finding that was in accordance with ESC guide- approximately 5% of patients switched from prasugrel or lines. At 6 and 12 months, β-blocker prescriptions decreased ticagrelor to clopidogrel. The TROPICAL-ACS and TOPIC in patients with preserved LVEF. National registry stud- studies demonstrated that switching from a novel P2Y12 ies have challenged the usefulness of long-term β-blocker inhibitor to clopidogrel was safe for ischemic endpoints and treatment in patients with ACS with preserved LVEF Percentage Optimal Medical Therapy After Acute Coronary Syndrome 227 in the PCI era [19, 20]. Five ongoing randomized trials per guidelines. The incidence of bleeding and dyspnea as a (AβYSS, NCT03498066; BETAMI, NCT03646357; DAN- reason for discontinuation of P2Y12 inhibitors corresponds BLOCK, NCT03778554; REBOOT-CNIC, NCT03596385; with results from another Dutch registry [31]. ACEi/ARBs REDUCE-SWEDEHEART, NCT03278509) are studying were stopped in 27% and 20%, respectively. Although not the effect of β-blocker withdrawal on hard clinical endpoints all reasons for withdrawal were known, the rate of ACEi in patients with ACS. Our study showed that discharge discontinuation because of cough (3.3%) was comparable ACEi/ARB prescriptions in patients with a class IA indica- with that in other reports (4.2–5.1%) [32, 33]. Statin-related tion were 63.7% in patients with STEMI and 72.1% in those myalgia or myopathy was the most reported side effect with NSTEMI, which later increased to 86.7 and 79.3% at 1 (4.5%). The discontinuation rate in our study was lower than month, respectively. Room for improvement of ACEi/ARB in randomized and observational studies, ranging from 8.8 treatment during the first month may still exist since most of to 12.0% [34–36]. However, statin users in these studies had their benefit is observed during the first week [21]. both primary and secondary prevention indications. Possi- bly, muscle-related statin discontinuation is lower in second- 4.4 Subgroups ary than in primary prevention because patients who have experienced a cardiovascular event are more willing to per- While OMT prescription at discharge did not differ between sist with (less intensive) statins, despite muscle symptoms. STEMI and NSTEMI, it was lower in patients with NSTEMI at 1 and 6 months. In particular, antiplatelet and statin ther-4.6 Limitations apy rates were lower in patients with NSTEMI. Patients with NSTEMI more often had a higher risk profile that included Several limitations of this study should be addressed. First, diabetes mellitus and previous cardiovascular events, indi- this was an observational study in two PCI centers and may cating a risk–treatment paradox that has been previously not reflect practice elsewhere. Second, the limited sample reported in patients with NSTEMI [22, 23]. size and missing data for several baseline characteristics pre- Additionally, OMT prescription was lower among vented us from analyzing a relation between OMT and out- women, which was also observed in other studies [24, 25]. come. We were only able to obtain mortality data through the Our results showed this difference was caused by lower Dutch national population registry and were unable to report P2Y12 inhibitor and statin use in women. In the PLATO other important clinical outcomes such as cause of death, trial, female sex was independently associated with major recurrent MI, or revascularization. Third, during follow-up, bleeding [26]. This could explain the difference in P2Y12 the number of patients with known medication decreased, inhibitor use at discharge and 1 month. It has been reported which could be a potential cause of bias. Fourth, the date of that women stopped a statin more often than men because of P2Y12 inhibitor cessation was not available, and we only side effects associated with statins, but women also received collected DAPT prescription data at 1, 6, and 12 months post- less information related to their cardiovascular risk profile discharge. Therefore, we could not calculate the exact DAPT and so may have been unaware of the importance of statin duration and were unable to determine the number of patients therapy [27]. who completed almost 12 months of DAPT (i.e., 335–364 Likewise, the decreasing trend in OMT prescription that days). Finally, we did not account for multiple testing. was observed in the elderly could also be explained by a decrease in antiplatelet therapy and statins. Age is an impor- tant risk factor, and short-term DAPT may be more benefi-5 Conclusions cial in elderly patients [28]. Although the benefits of statin therapy in elderly patients are clear, the treatment–benefit In this pilot study that aimed to extend the national Dutch ratio of statins should be evaluated according to patients’ ACS registry to patients with STEMI and NSTEMI, OMT life expectancy [29]. Nevertheless, in the current aging ACS prescription was comparable to other local registries and was population, it remains important to know that OMT prescrip- lower in women and patients with NSTEMI and decreased tion is associated with a survival benefit in all ages [30]. with age. Acknowledgements The authors thank Ruben de Winter, Shahla 4.5 Discontinuation Ajoebi, and Wesley van den Busken for their assistance with the devel- opment of the registry database. We assessed drug discontinuation in one of the participat- Declarations ing centers that recorded reasons for withdrawal and found discontinuation was highest for P2Y12 inhibitors and ACEi/ Funding This study was funded by an unrestricted research grant from ARBs. As expected, P2Y12 inhibitors were mostly stopped AstraZeneca Netherlands B.V. because DAPT, triple, or dual therapy treatment ended as 228 N. P. G. Hoedemaker et al. Conflict of interest P. Damman has received an unrestricted research The Task Force for dual antiplatelet therapy in coronary artery grant from AstraZeneca Netherlands B.V. Niels PG Hoedemaker, Rob- disease of the European Society of Cardiology (ESC) and of the bert J de Winter, Arnoud van ’t Hof, and Evelien Kolkman have no European Association for Cardio-Thoracic Surgery (EACTS). Eur potential conflicts of interest that might be relevant to the contents of Heart J. 2018;39(3):213–60. this manuscript. 6. Ozcan C, Juel K, Flensted Lassen J, von Kappelgaard LM, Mortensen PE, Gislason G. The Danish Heart Registry. Clin Epi- Ethics approval This study was conducted with a waiver from the med- demiol. 2016;8:503–8. ical ethical committee of the Academic Medical Center in Amsterdam. 7. Jernberg T, Attebring MF, Hambraeus K, Ivert T, James S, Jepps- According to Dutch law applicable at the time of the study period, son A, et  al. The Swedish Web-system for enhancement and written informed consent for the conduction of this registry study was development of evidence-based care in heart disease evaluated not required. according to recommended therapies (SWEDEHEART). Heart. 2010;96(20):1617–21. Consent to participate Not applicable. 8. Bebb O, Hall M, Fox KAA, Dondo TB, Timmis A, Bueno H, et al. Performance of hospitals according to the ESC ACCA qual- Consent for publication Not applicable. ity indicators and 30-day mortality for acute myocardial infarc- tion: national cohort study using the United Kingdom Myocardial Availability of data and material Not applicable. Ischaemia National Audit Project (MINAP) register. Eur Heart J. 2017;38(13):974–82. Code availability Not applicable. 9. Hoedemaker NP, Ten Haaf ME, Maas JC, Damman P, Appelman Y, Tijssen JG, et al. Practice of ST-segment elevation myocardial infarction care in the Netherlands during four snapshot weeks with Open Access This article is licensed under a Creative Commons Attri- the National Cardiovascular Database Registry for Acute Coro- bution-NonCommercial 4.0 International License, which permits any nary Syndrome. Neth Heart J. 2017;25(4):264–70. non-commercial use, sharing, adaptation, distribution and reproduction 10. 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American Journal of Cardiovascular DrugsSpringer Journals

Published: Aug 12, 2020

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