Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

When, and when not, to use digoxin in the elderly

Digitalis has been widely used in the treatment of cardiac disease for more than 200 years. The present article reviews the current role of digitalis in the management of heart failure and atrial fibrillation (AF) in light of recent study findings. Generally, first-line therapy for the management of heart failure due to systolic dysfunction should include an ACE inhibitor and a diuretic. In patients who remain symptomatic despite the use of these drugs, the addition of digoxin should be considered. Because digoxin has been shown to reduce the number of hospital admissions attributable to worsening heart failure, more liberal use of digoxin in the management of heart failure may be justified. Digoxin may be adequate as monotherapy for ventricular rate control in patients with chronic AF, particularly in sedentary and elderly patients. A beta-blocker or calcium antagonist (either alone or in combination with digoxin) is indicated when digoxin is ineffective for ventricular rate control. Digoxin is ineffective in restoring sinus rhythm, preventing paroxysms or controlling rate in paroxysmal AF. The elderly are at an increased risk of digoxin toxicity. Low dosages of digoxin appear to be effective in the treatment of heart failure due to systolic dysfunction and may reduce the incidence of digitalis toxicity in these patients. In elderly patients with AF and inadequate rate control who are receiving digitalis monotherapy, adding another atrioventricular nodal blocking drug may be more appropriate than increasing the digoxin dose, in order to avoid toxic digoxin levels

Acute pericarditis presenting with sinus bradycardia: A case report

Acute pericarditis is almost invariably associated with sinus tachycardia. Recent-onset chest pain in the presence of (sinus) bradycardia is considered to be associated with an acute ischemic syndrome rather than acute pericarditis. This report describes a patient with acute pericarditis initially presenting with sinus bradycardia, probably due to a vasovagal response to (chest) pain. (C) 1997 Elsevier Science Ireland Ltd

COMPARISON IN THE SAME PATIENT OF ABERRANT CONDUCTION AND BUNDLE-BRANCH REENTRY AFTER DOFETILIDE, A NEW SELECTIVE CLASS-III ANTIARRHYTHMIC AGENT

Dofetilide may induce aberrant intraventricular conduction due to its Class III effect. This report describes an atrial fibrillation patient in whom intraventricular conduction was studied before and after dofetilide using multiple endocardial recordings. Dofetilide provoked aberrant conduction during atrial fibrillation, and aberrancy could be mimicked with programmed atrial stimulation after restoration of sinus rhythm. However, during right ventricular stimulation, isolated bundle branch reentrant beats were recorded after induction of critical retrograde conduction delays. This occurred in the setting of relatively large differences in refractoriness between the right bundle branch and the right ventricular myocardium. This favored distal retrograde bundle branch block during ventricular extrastimulation, in turn enhancing bundle branch reentry. This potential proarrhythmic mechanism deserves close attention in the further development of dofetilide and also of other new ''pure'' Class III agents

EXERCISE-INDUCED VENTRICULAR-TACHYCARDIA - A RARE MANIFESTATION OF DIGITALIS TOXICITY

Digitalis intoxication is one of the most common adverse drug reactions. Although some arrhythmias are seen more frequently than others, virtually any rhythm disturbance, including ventricular tachycardia, may occur. However, to our knowledge, exercise-induced ventricular tachycardia as a complication of digitalis therapy has never been described before. This case presents a patient with a digitalis-induced ventricular tachycardia occurring exclusively during exercise

Alteration of peripheral vasodilatory reserve capacity after cardioversion of atrial fibrillation

In atrial fibrillation, exercise capacity is often reduced. This is usually ascribed to a decreased cardiac output as coin compared with sinus rhythm. Very few studies, however, have focused oil changes in the peripheral blood flow during atrial fibrillation as a potential mechanism for exercise limitation. The aim of the present study was to determine the effect of conversion of atrial fibrillation to sinus rhythm on peripheral blood flow. Calf blood flow, using an electrocardiogram-triggered venous occlusion plethysmograph, and peak oxygen consumption (peak VO2), using treadmill exercise testing, were studied in 28 patients with chronic atrial fibrillation eligible for electrical cardioversion. Measurements were performed before cardioversion, and repeated 1 day and 1 month thereafter. Calf blood flow at rest, maximal calf blood flow, and minimal calf vascular resistance during the hyperaemic response immediately following 700 J of calf exercise were determined plethysmographically. One day and 1 month after cardioversion, 23 and 14 patients were still in sinus rhythm, respectively. In patients who still had sinus rhythm after 1 month, maximal calf blood Bow increased from 37.7 +/- 12 to 40.0 +/- 13 ml. 100 ml(-1 min-1) (P <0.01) and minimal calf vascular resistance fell from 3.2 +/- 0.9 to 2.7 +/- 0.7 mmHg. ml(-1). 100 ml(-1). min(-1) (P <0.01); peak VO2 increased from 21.3 +/- 4 to 24.2 +/- 5 ml. min(-1). kg(-1) (P <0.001). Calf blood flow at rest did not improve. In contrast, no significant changes in maximal calf blood flow, minimal calf vascular resistance and peak VO2 occurred in patients who had atrial fibrillation 1 month after cardioversion. A significant correlation was found between changes in maximal calfs blood now and peak VO2 1 month after cardioversion (r = 0.53, P <0.01). One day after cardioversion, no changes in calf blood flow or peak VO, were found, either in patients with sinus rhythm or atrial fibrillation. In conclusion, transition from chronic atrial fibrillation to sinus rhythm is associated with a (delayed) improvement in maximal calf blood flow, minimal calf vascular resistance, and peak VO2. Our findings suggest thai increase in vasodilatory reserve capacity may contribute in the improvement of exercise capacity after cardioversion of atrial fibrillation