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dial remodeling and fibrosis, as well as sodium retention and potassium loss at the distal tubules Thus, spironolactone should be considered as a neurohormonal antagonist rather than narrowly as a potassium-sparing diuretic The RALES trial compared spironolactone 25 mg daily with placebo in patients with advanced heart failure (current or recent class IV) already receiving ACE inhibitors and diuretics and showed a 29% reduction in mortality as well as similar decreases in other clinical end points Hyperkalemia was uncommon in this severe heart failure clinical trial population, which was maintained on high doses of diuretic, but hyperkalemia with spironolactone appears to be common in general practice Potassium levels should be monitored closely during initiation of spironolcatone (after 1 and 4 weeks of therapy), particularly for patients with even mild degrees of renal insufficiency, and in patients receiving ACE inhibitors Neither the efficacy nor the safety of spironolactone has been established in the large majority of patients with mild or moderate heart failure who are taking low doses of diuretics, though this agent may be considered in patients who require potassium supplementation It is not known whether the more selective aldosterone inhibitor, eplerenone, is effective in improving outcome in chronic heart failure 3 -Blockers -Blockers are part of the foundation of care of chronic heart failure based on their life-saving benefits The mechanism of this benefit remains unclear, but it is likely that chronic elevations of catecholamines and sympathetic nervous system activity cause progressive myocardial damage, leading to worsening LV function and dilation The primary evidence for this hypothesis is that over a period of 3 6 months, -blockers produce consistent substantial rises in EF (averaging 10% absolute increase) and reductions in LV size and mass Clinical trial results have been reported in nearly 14,000 patients (ranging from asymptomatic post-myocardial infarction LV dysfunction to severe heart failure with LV EFs < 35 40%) receiving ACE inhibitors and diuretics randomized to blockers or placebo Carvedilol, a nonselective 1- and 2receptor blocker with additional weak -blocking activity, was the first -blocker approved for heart failure in the United States after showing a reduction in death and hospitalizations in four smaller studies with a total of nearly 1100 patients Subsequently, trials with two 1-selective agents, bisoprolol (CIBIS II, with 2647 patients) and sustained-release metoprolol succinate (MERIT, with nearly 4000 patients), showed 35% reductions in mortality as well as fewer hospitalizations A trial using carvedilol in 2200 patients with severe (NYHA class III/IV) heart failure was terminated ahead of schedule because of a 35% reduction in mortality In these trials, there were reductions in sudden deaths and deaths from worsening heart failure, and benefits were seen in patients with underlying coronary disease and those with primary cardiomyopathies In all these studies, the -blockers were generally well tolerated, with similar numbers of withdrawals in the active and placebo groups This has led to a strong recommendation that stable patients (defined as having no recent deterioration or evidence of volume overload) with mild, moderate, and even severe heart failure should be treated with a -blocker unless there is a noncardiac contraindication In the COPER-.

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(Sales document type SO) For the rush order process the customer places the order and collects the items immediately, or the materials are shipped immediately However, the customer is invoiced later The system automatically creates a delivery when the sales order is saved However, no invoice is printed; instead the system follows the standard procedures for creating the billing document (that is, the invoice is created once the delivery has been goods issued) Both the rush order process and the cash sale process utilize the shipping conditions passed on from the sales document The shipping conditions in turn are used to determine the shipping point and the route The only difference between a rush order and a standard order is that the rush order has an immediate delivery creation This delivery, however, may still need to progress through the logistics process of picking, packing, loading, and goods issue processing

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