Summary
Background
Heart rate is a major determinant of myocardial oxygen demand; in ST-segment elevation myocardial infarction (STEMI), patients treated with primary percutaneous intervention (PPCI), heart rate at discharge correlates with mortality. Ivabradine is a pure heart rate-reducing agent that has no effect on blood pressure and contractility, and can reverse left ventricular (LV) remodelling in patients with heart failure.
Aims
To evaluate whether ivabradine, when added to current guideline-based therapy, improves LV remodelling in STEMI patients treated with PPCI.
Methods
This paired-cohort study included 124 patients between June 2011 and July 2012. Ivabradine (5 mg twice daily) was given promptly after PPCI, along with beta-blockers, to obtain a heart rate < 60 beats per minute (ivabradine group). This group was matched with STEMI patients treated in line with current guidelines, including beta-blockers (bisoprolol), according to age, sex, infarct-related coronary artery, ischaemia time and infarct size determined by initial cardiac magnetic resonance imaging (CMR) (control group). Statistical analyses were performed according to an intention-to-continue treatment principle. CMR data at 3 months were available for 122 patients.
Results
Heart rate was lower in the ivabradine group than in the control group during the initial CMR ( P = 0.02) and the follow-up CMR ( P = 0.006). At the follow-up CMR, there was a smaller increase in LV end-diastolic volume index in the ivabradine group than in the control group ( P = 0.04). LV end-systolic volume index remained unchanged in the ivabradine group, but increased in the control group ( P = 0.01). There was a significant improvement in LV ejection fraction in the ivabradine group compared with in the control group ( P = 0.04).
Conclusions
In successfully reperfused STEMI patients, ivabradine may improve LV remodelling when added to current guideline-based therapy.
Résumé
Contexte
La fréquence cardiaque est un déterminant majeur de la demande en oxygène du myocarde. Chez les patients, ayant présenté un syndrome coronarien aigu avec sus-décalage du segment ST, revascularisés par une angioplastie primaire percutanée, la fréquence cardiaque à la sortie de l’hôpital est corrélée à la mortalité. L’ivabradine est un pur agent bradycardisant et n’a pas d’effet sur la pression artérielle et la contractilité myocardique ; l’ivabradine peut inverser le remodelage ventriculaire gauche chez le patients atteints d’insuffisance cardiaque.
Objectifs
Évaluer si l’ivabradine, ajouté aux traitements habituellement recommandés, améliore le remodelage ventriculaire gauche chez des patients ayant présenté un syndrome coronarien aigu avec sus-décalage du segment ST qui ont été revascularisés par une angioplastie primaire percutanée.
Méthodes
Cette étude de cohorte appariée a inclus 124 patients entre juin 2011 et juillet 2012. L’ivabradine à la dose de 5 mg deux fois par jour a été administrée rapidement après l’angioplastie primaire percutanée de manière concomitante aux bêta-bloquants pour obtenir une fréquence cardiaque inférieure à 60/min (le groupe ivabradine). Ce groupe a été apparié avec d’autres patients ayant présenté un syndrome coronarien aigu avec sus-décalage du segment ST, traités selon les recommandations incluant des bêta-bloquants (le groupe témoin). Les 2 groupes étaient appariés selon l’âge, le sexe, l’artère responsable de l’infarctus, le temps d’ischémie et la taille de l’infarctus déterminé par l’IRM initiale. L’analyse statistique était réalisée en intention de continuer le traitement. Les données IRM étaient disponibles pour 122 patients.
Résultats
La fréquence cardiaque était inférieure dans le groupe ivabradine par rapport au groupe témoin lors de l’IRM initiale ( p = 0,02) et de l’IRM de contrôle ( p = 0,006). Lors du suivi IRM, un traitement par ivabradine était associé à une moindre augmentation du volume télédiastolique ventriculaire gauche indexé que dans le groupe témoin ( p = 0,04). Dans le groupe ivabradine, le volume télésystolique ventriculaire gauche indexé était inchangé alors qu’il augmentait dans le groupe témoin ( p = 0,01). Il y avait une amélioration significative de la fraction d’éjection ventriculaire gauche dans le groupe ivabradine par rapport au groupe témoin ( p = 0,04).
Conclusion
Chez les patients reperfusés avec succès après un infarctus du myocarde, l’ivabradine associé aux traitements habituellement recommandés peut améliorer le remodelage ventriculaire gauche.
Background
Acute myocardial infarction (AMI) induces scar formation and changes in the surviving myocardium, designated as post-AMI ventricular remodelling . Adverse left ventricular (LV) remodelling, defined as an increase in LV end-systolic volume (LVESV) is associated with progression to heart failure and poor outcome. The therapeutic effects of beta-blockade, angiotensin-converting enzyme inhibition and mineralocorticoid receptor antagonist (MRA) inhibition have been linked to their beneficial effects on cardiac remodelling . Thus, oral treatment with beta-blockers should be considered during hospital stay and continued thereafter in all patients with ST-segment elevation myocardial infarction (STEMI) . Heart rate (HR) is a major determinant of myocardial oxygen demand. Furthermore, in STEMI patients treated with primary percutaneous intervention (PPCI), HR at discharge has been found to correlate with mortality .
Ivabradine is a pure HR reducing agent that has no effect on blood pressure and contractility. The results of the Systolic Heart failure treatment with the I f inhibitor ivabradine Trial (SHIFT) showed that an HR decrease with ivabradine reversed LV remodelling in patients with heart failure . In the same way, ivabradine improved the LV pressure-volume relationship, decreased interstitial collagen content and increased capillary density in young adult rats with AMI and congestive heart failure . Only one trial has investigated the effects of ivabradine versus beta-blockers in early phases of anterior STEMI with impaired LV function treated with PPCI . In this study, at 2-month follow-up, patients treated with ivabradine had a significant increase in LV ejection fraction (LVEF), with concomitant reduction in LVESV and LV end-diastolic volume (LVEDV). However, to our best knowledge, no study has evaluated the additional value of ivabradine in STEMI patients treated with successful PPCI and optimal medical therapy. Therefore, our study was designed specifically to evaluate whether ivabradine improves LV remodelling after AMI when added to current guideline-based therapy, including beta-blockers, in STEMI patients treated with successful PPCI.
Methods
We decided to conduct a non-randomized study because we felt we did not have enough strong preliminary scientific data on the use of ivabradine in humans during the acute phase of myocardial infarction. However, in view of the experimental data, we wanted to conduct a pilot study to assess the feasibility and impact on LV remodelling of adding ivabradine to standard pharmacological therapy following PPCI in patients presenting with STEMI.
Patients
This paired-cohort study was approved by the ethics committee of our institution and all patients gave their written informed consent before inclusion. Between June 2011 and July 2012, all consecutive patients presenting with a STEMI were considered eligible for participation. Among them, two matched groups were formed: the ivabradine group and the control group. Inclusion criteria were: the presence of an inaugural STEMI, defined by prolonged chest pain, troponin T concentration higher than twice the upper limit (> 0.01 ng/mL) and electrocardiogram changes on at least two contiguous leads with pathological Q waves (> 0.04 seconds) and/or persisting ST-segment elevation (> 0.1 mV); and successful reperfusion (Thrombolysis in Myocardial Infarction [TIMI] flow grade 3 in the infarct-related artery). Exclusion criteria were: unsuccessful myocardial reperfusion (TIMI flow grade ≤ 2); thrombolysis; haemodynamic instability; atrial arrhythmia; HR < 70 beats per minute (b.p.m.) 1 hour after coronary angioplasty; and contraindications to cardiac magnetic resonance imaging (CMR). The ivabradine group was matched with a control group of STEMI patients according to age, sex, infarct-related coronary artery, ischaemia time and infarct size determined by initial CMR.
Emergency care and percutaneous procedure
During transport for percutaneous coronary intervention (PCI), all patients received intravenous low-molecular-weight heparin (enoxaparin; 0.5 mg/kg), intravenous aspirin (≥ 250 mg) and loading doses of clopidogrel (≥ 600 mg) or prasugrel (≥ 60 mg). All patients underwent PPCI with bare-metal and/or drug-eluting stent implantation in the culprit artery. A glycoprotein IIb/IIIa inhibitor (abxicimab) was administered during the procedure, at the discretion of the operator. Thrombus aspiration before stent implantation of the infarct-related coronary artery was performed, according to the guidelines . Coronary flow before and after revascularization was graded according to the TIMI study group classification by two blinded observers (25 and 10 years of experience in coronary angiography, respectively). A successful procedure was defined when both TIMI grade 3 and residual diameter stenosis < 30% were obtained.
Study plan and treatments
Patients were assigned to a treatment group, according to the decision (free choice) of the cardiologist in charge at admission to the intensive care unit after the coronary angioplasty. The study plan is presented in Fig. 1 . Between 1 and 3 hours after angioplasty, patients in the ivabradine group and presenting with HR ≥ 70 b.p.m. received a 5 mg test dose of ivabradine to evaluate their tolerance; ivabradine was then given orally at the 5 mg dose, twice daily. A concomitant beta-blocker (bisoprolol) was given and uptitrated to 10 mg to reach the target HR i.e. < 60 b.p.m. during hospitalization. Other therapies, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and MRAs if considered appropriate, were optimized in accordance with contemporary guidelines. If the resting HR was < 50 b.p.m. or the patient experienced symptoms related to bradycardia, the dose of ivabradine was reduced to 2.5 mg, twice daily. LV volume and mass, LVEF, myocardial wall thickness in infarct and remote non-infarcted myocardium and infarct size were assessed in all patients by performing CMR during hospitalization. The control group included patients treated according to current guidelines , including beta-blockers (bisoprolol in our centre), to obtain a HR < 60 b.p.m. at discharge. In our institution, all these patients were evaluated using initial CMR a few days after AMI and follow-up CMR at 3 months.
CMR protocol and analysis
CMR studies were performed on a 1.5 T clinical scanner equipped with a 32-channel cardiac coil (Avanto; Siemens Medical Solutions, Forchheim, Germany). Cine imaging was performed to acquire a stack of short-axis slices covering the whole of the left ventricle (LV) from base to apex, using an electrocardiogram-gated balanced steady-state free-precession breath-hold sequence with the following parameters: repetition time/echo time 20–30/1.4 ms; flip angle 60°; slice thickness 6 mm; pixel size 1.6 × 1.6 to 1.8 × 1.8 mm; 20 frames per cardiac cycle. Late gadolinium-enhanced imaging was performed to acquire a stack of short-axis slices covering the whole LV from base to apex. Acquisition was initiated 15 minutes after the injection of 0.2 mmol/kg gadoterate meglumine (Dotarem; Guerbet, Aulnay-Sous-Bois, France) using an inversion-recovery-prepared three-dimensional turbo fast low-angle shot breath-hold sequence with the following parameters: TR/TE 700/1.4 ms; flip angle 10°; slice thickness 6 mm; pixel size 1.8 × 1.4 mm. Inversion time was optimized on a previously-acquired TI scouting sequence . Data were exported to a separate workstation for analysis using a commercially available software package (MASS version 7.0; Medis Medical Imaging Systems, Leiden, The Netherlands). Image segmentation was performed by two observers (with 12 and 2 years of experience in CMR, respectively) blinded to clinical data, including the treatment with ivabradine. Endocardial and epicardial contours were segmented on end-diastolic and end-systolic frames at each short-axis location. LV trabeculae and papillary muscles were included in the ventricular volume . LVEDV and LVESV were computed in millilitres using the modified Simpson’s rule and were used to calculate LVEF, expressed as a percentage. Adverse LV remodelling was defined as an increase in LVESV ≥ 15% at follow-up . LV mass (in grams) was calculated from the total volume of myocardium at end diastole multiplied by the myocardial density of 1.05 g/mL. LV volumes were indexed to body surface area. Delayed-enhanced short-axis images were segmented at a different time point by the same observers. Endo- and epicardial contours were manually traced and myocardial scar was automatically segmented, with a threshold set at 50% maximal signal intensity .
Statistical analysis
Continuous data are expressed as means ± standard deviations when they followed a normal distribution and as medians (interquartile ranges) when they did not. Categorical data are expressed as absolute values (percentages). Statistical analyses were performed according to an intention-to-continue treatment principle. When follow-up CMR data were missing, they were replaced by values reflecting: increased LVEDV and LVESV of 20%; decreased myocardial wall thickness in infarct myocardium and decreased LV mass of 10%. Clinical and paraclinical characteristics were compared between the two groups using two-sampled t tests (or their non-parametric equivalents, i.e. the Mann-Whitney test and the signed-rank Wilcoxon’s test). Two-sampled t tests were also used to compare changes in continuous variables from initial CMR to follow-up CMR between the two groups. Comparison of categorical variables was achieved using the chi-square test or Fisher’s exact test. All statistics were calculated using NCSS and PASS software (NCSS 2001; NCSS Statistical Software, Kaysville, Utah). P values < 0.05 were considered significant.
Results
Population
Of 456 STEMI patients screened, 170 patients satisfied all the inclusion and exclusion criteria. These patients, according to the decision of the cardiologist in charge, were assigned to either the ivabradine group or the control group. Among them, 124 Caucasian patients were matched, to form two groups ( Fig. 2 ). The final analysis included 124 patients whose characteristics are reported Table 1 .
| Ivabradine ( n = 62) | Control ( n = 62) | P | |
|---|---|---|---|
| Mean age (years) | 56.7 ± 11.7 | 58.2 ± 10.5 | 0.45 |
| Men | 56 (90.3) | 55 (88.7) | 0.77 |
| Family history of premature heart disease | 25 (40.3) | 28 (45.2) | 0.59 |
| Hypertension a | 23 (37.1) | 26 (41.9) | 0.58 |
| Smokers | 43 (69.3) | 42 (67.7) | 0.85 |
| Hyperlipidaemia b | 42 (67.7) | 40 (64.5) | 0.45 |
| Body mass index (kg/m 2 ) | 26.7 (24.5–29.0) | 26.2 (23.4–28.4) | 0.23 |
| Diabetes mellitus | 14 (22.6) | 12 (19.3) | 0.66 |
| Ischaemia time (minutes) | 294 ± 182 | 291 ± 169 | 0.79 |
| Coronary angiography | |||
| Infarct-related artery | 0.81 | ||
| LAD | 29 (46.8) | 27 (43.5) | |
| LCx | 12 (19.4) | 15 (24.2) | |
| RCA | 21 (33.8) | 20 (32.3) | |
| Single-vessel disease c | 22 (35.5) | 23 (37.1) | 0.91 |
| Double-vessel disease c | 23 (37.1) | 23 (37.1) | 1.0 |
| Triple-vessel disease c | 17 (27.4) | 16 (25.8) | 0.73 |
| TIMI flow grade ≥ 2 before PCI | 16 (25.8) | 12 (19.4) | 0.39 |
| Medication at follow-up (3 months) | |||
| Aspirin | 62 (100) | 62 (100) | 1.0 |
| ADP receptor inhibitors | 62 (100) | 62 (100) | 1.0 |
| ACEi or A2 receptor blockers | 61 (98.4) | 59 (95.2) | 0.31 |
| MRA | 9 (14.5) | 10 (16.1) | 0.80 |
| Beta-blocker | 62 (100) | 62 (100) | 1.0 |
| Beta-blocker dosage (mg/day) d | 4.0 (2.5–5) | 4.2 (2.5–5) | 0.84 |
| Statins | 62 (100) | 62 (100) | 1.0 |
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