الفهرس 
Acute coronary syndromesOnly 14 pages are availabe for public view
Abstract
Heart rate is an independent risk predictor of the onset of acute coronary events. Many epidemiological and clinical studies aimed to explore the association between resting HR and outcomes in healthy and cardiovascular diseased patients. Elevated resting HR multiplies risk and interferes at all phases of the cardiovascular disease spectrum, initiating from endothelial dysfunction and passing through atherosclerotic lesion formation and plaque rupture to end-stage cardiovascular disease.
In animal studies, sustained elevation of HR was associated with vascular oxidative stress, endothelial dysfunction, acceleration of atherogenesis, and vascular stiffness. Experimental data also suggested that a reduction in HR can delay the progression of coronary atherosclerosis.
Clinical studies revealed a relation between accelerated resting HR, systemic inflammation and markers of endothelial dysfunction. There exist a strong positive relationship between higher HR and the extent of atherosclerotic coronary lesions in young patients with MI. A higher HR may itself directly induce an inflammatory response through an increased frequency of mechanical stress on the vascular endothelium.
Ivabradine, an If current inhibitor, induces a sustained and dose-dependent HR reduction at rest and during exercise, with no relevant effects on contractility, blood pressure or atrioventricular conduction. Treatment with ivabradine reduced vascular oxidative stress and inflammation, restored endothelial function, and augmented vascular compliance in ApoE deficient mice.
The anti-anginal and anti-ischemic efficacy of ivabradine–in monotherapy or in combination with a β-blocker–has been demonstrated by several clinical trials. As a consequence, the substance evolved as an alternative strategy particularly for patients in whom the use of β-blockers is contraindicated, intolerable or patients who remain symptomatic despite β -blockade.
In Europe, It is approved and indicated for the symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm who cannot take β-blockers. It is also indicated in combination with β-blockers in heart failure patients with left ventricular dysfunction inadequately controlled by β-blockers alone and whose HR exceeds 70 bpm. In the United States, Food and Drug Administration approved Ivabradine use only in heart failure.
C-reactive protein (CRP) is a sensitive marker of inflammation. Increased levels of high-sensitivity C-reactive protein (hsCRP) are associated with endothelial dysfunction; reflect subclinical inflammatory states such as vascular inflammation, and predict future cardiovascular risk.
In patients with ACS, higher hsCRP levels are associated with adverse outcomes and subsequent vascular events. Clinical studies showed that the achieved level of hsCRP after ACS treatment is an independent predictor of consequent outcomes. Accordingly additional interventions aiming at lowering CRP in post-ACS may provide additive benefit in this high-risk subgroup of patients.
Since increased HR may contribute to endothelial dysfunction by up-regulation of inflammatory cytokines, we expect that HR lowering by ivabradine may decrease inflammation in patients with ACS. The primary purpose of this study is to examine the effect of HR lowering by ivabradine on hsCRP levels in patients with NSTE-ACS.
The current study is a prospective, randomized, controlled, study. It was carried out in the Cardiology Intensive Care Unit, Department of Cardiology, Ain Shams University Hospitals, Cairo, Egypt.
The included patients were above 18 years, presenting with typical ischemic chest pain occurring at rest or with minimal effort (>10 min) with ECG changes revealing new ischemia or ST elevation or elevated cardiac enzymes or biomarkers Patients were in sinus rhythm with a resting HR of ≥ 70 bpm on a resting standard 12-lead ECG. The included patients were admitted to the unit within 12 hours of symptom onset. Patients were excluded if there was a history of myocardial infarction, coronary revascularization, stroke, or transient ischemic attack within the preceding 3 months.
A total of 45 consecutive NSTE-ACS patients were recruited from September 2013 to October 2014. Each was randomly assigned to either the ivabradine (23 patients) or the control (22 patients) group. All patients received the conventional cardiovascular treatment including: β-blockers, nitrates, statins, antiplatelet drugs, and antithrombin therapy according to the European Society of Cardiology (ESC) Guidelines for the management of ACS. Bisoprolol 2.5, 5, 10 (Concor®/ Concor®cor, Merck Serono, Darmstadt, Germany) was the β-blocker used in this study.
Patients in the ivabradine group received ivabradine (Procoralan®, Les Laboratoires Servier Industrie - France) 5mg twice daily starting from day two after admission and during 30 days plus the previously mentioned medications required for the management of ACS. Patients who received 5 mg twice daily for a week after inclusion with a resting HR of ≥ 70 bpm had their dose increased to 7.5 mg twice daily till the end of 30 days.
After obtaining the informed consent, baseline evaluation was performed and all medications received by the patients were recorded.
Thorough clinical examination was done for every patient with assessment of HR, blood pressure, and standard 12-lead ECG and echocardiogram. The GRACE score was calculated on admission and discharge to estimate the in-hospital and 6-months outcomes.
Blood samples were withdrawn from patients for evaluation of hsCRP was done once within 24 - 48 hours of symptom onset. Fasting total cholesterol, LDL and HDL cholesterol were estimated. Liver and renal function tests were performed as part of the routine admission care.
All patients were followed up for 30 days. Follow-up visits were scheduled to see each patient once per week and on day 30. Each follow up visit included assessment of ischemic events, of recent medical history since the last follow-up appointment, recording the occurrence of major adverse cardiovascular events (MACE: death, nonfatal myocardial infarction, unstable angina, urgent revascularization, stroke, hospitalization for HF, arrhythmias, or cardiac arrest), documentation of concomitant medications and records of adverse drug effects. Medical examination including determination of HR and a standard 12-lead ECG was carried out. Evaluation of compliance with study medication by pill count was obtained at all study visits. The 30-day visit included as well laboratory reassessment of hsCRP, fasting blood lipids, creatinine, and ALT.
The current study showed the following:
• The reduction in HR was significantly larger in the ACS patients who received ivabradine in addition to bisoprolol
• A trend toward larger reduction in hsCRP levels after 30 days of treatment with ivabradine
• Positive correlation between HR and hsCRP reduction was observed
• No effects of therapy on lipid profile was obtained
• Ivabradine did not affect the short-term clinical outcome of ACS patients
• Ivabradine was well tolerated up to 7.5 mg bid in the study patients
Conclusion:
Hence it is concluded that addition of ivabradine effectively reduced HR in NSTE-ACS patients. The administration of ivabradine seems to be safe within the used dose. The positive correlation between HR and hsCRP reduction warrants the performance of large randomized clinical trial for further assessment of HR lowering effects on inflammation and cardiovascular outcome in ACS patients.
Recommendations:
• It is recommended that more extensive and multi-centric clinical trials are to be conducted to better demonstrate the effect of ivabradine on inflammation and clinical outcome in ACS patients.
• The use of ivabradine should be studied in large randomized controlled studies to determine the cost effectiveness of its use in ACS patients
• Firm protocols that ensure patient compliance to treatment and follow-up visits should be established
• Separate studies on patients with different subgroups of ACS and various risk factors for MACE should be conducted individually.