Placebos with ACES

Captopril (Capoten) was the original prototype product, and it was administered three times a day. A once-a-day preparation was subsequently patented and marketed. Prospective multicenter double-blind placebo-controlled clinical trials have repeatedly demonstrated an early and persistent survival benefit with ACE inhibitors in CHE patients. ACE inhibitors were found superior to hydralazine and nitrates in a direct comparison. ACE inhibitors are now clearly the agents of first choice in the pharmacological management of CHE There are also a number of additional reasons to use ACE inhibitors. The HOPE trial and other studies demonstrated additional survival and renal protective benefits of ACE inhibition in diabetic and/or hypertensive patients long before they develop CHE. 

RALES (92) NYHA III-IV LVEF < 35% Treatment with ACE inhibitors and loop diuretics 1663 Spironolactone, 25-mg daily, vs. placebo Significant reduction of all causes of mortality absolute risk reduction 11 % lower risk of hospitalization for worsening HF... 

A compilation of three controlled trials in 1200 patients showed incidence rates of cough of 3.6% with valsartan versus 9.5% with ACE inhibitors and 0.4% with placebo (1). 

Two studies that compared the interaction of celecoxib with ACE inhibitors found no difference in blood pressure effects compared to placebo [58, 59]. In one study (n=359), the blood pressure (systohc and diastolic) effects of celecoxib 200 mg BID and nabumetone 1 g BID were found to be similar to placebo, but significantly different from ibuprofen 800 mg IID [58]. In the second study (n=178), the effects of celecoxib 400 mg daily and placebo on 24-hour blood pressure in hypertensive patients controlled on hsinopiil 10-40 mg daily was evaluated [59]. No difference between groups was observed in 24-hour ambulatory SBP. The difference between groups in 24-hour diastolic BP was only 1.4 mm Hg. The change from baseline in 24-hour blood pressure (1.8 mm Hg/1.4mm Hg) is less than what has been the effect of NSAIDs on the SBP (defined as an increase >20 mm Hg with an absolute value of >140 mm Hg) reported for traditional NSAIDs in ACE inhibitor-treated patients. On the other hand, co-ad-ministration of rofecoxib 25 mg daily with benazepril 10-40 mg for 4 weeks in patients with mild to moderate... 

The beneficial effect of ACE inhibitors on mortality has been documented conclusively, with numerous trials showing a 20% to 30% relative reduction in mortality with ACE inhibitor therapy compared with placebo. A long-term (12-year) follow-up of the Studies of Left Ventricular Dysfunction (SOLVD) prevention and treatment trials demonstrated sustained survival benefits in patients treated with enalapril. In addition to improving survival, ACE inhibitors also reduce the combined risk of death or hospitalization, slow the progression of heart failure, and reduce the rates of reinfarction.The benefits of ACE inhibitor therapy are independent of the etiology of heart failure (ischemic versus nonischemic) and are observed in patients with mild, moderate, or severe symptoms. ACE inhibitors clearly are superior to vasodilator therapy with hydralazine-isosorbide dinitrate. ... 

More recent data suggest that all patients with CAD, not just ACS or heart failure patients, benefit from an ACE inhibitor. In the Heart Outcome Prevention Evaluation (HOPE) trial, ramipril significantly reduced the risk of death, MI, or stroke in high-risk patients aged 55 years or older with chronic CAD or with diabetes and one cardiovascular risk factor. The more recent European trial On Reduction Of Cardiac Events With Perindopril In Stable Coronary Artery Disease (EUROPA) extended the benefit of chronic therapy with ACE inhibitors to patients with stable CAD at lower risk of cardiovascular events compared with patients from the HOPE trial. In the EUROPA trial, patients randomized to perindopril experienced a lower risk of the combined end point of cardiovascular death, MI, or cardiac arrest compared with patients randomized to placebo. Therefore, based on the extensive benefit of ACE inhibitors in patients with CAD, their routine use should be considered in all patients following an ACS in the absence of a contraindication. 

In an analysis of the Valsartan in Heart Failure Trial (Val-HeFT), focusing on chronic kidney disease, the benefits and harms of dual blockade of the RAAS have been explored [29. Compared with the addition of placebo to ACE inhibition, the addition of valsartan led to higher rates of discontinuation and hyperkalemia in those with chronic kidney disease at baseline. However, the authors argued that the overall benefits of combined therapy would outweigh the risks even in those with chronic kidney disease. 

More recently, the value of adding the combination of isosorbide dinitrate 40 mg and hydralazine 75 mg three times daily to therapy including ACE inhibitors, P-blockers, digoxin, and diuretics was evaluated in a prospective, randomized trial26 The study enrolled only African-American patients and demonstrated a significant reduction in mortality, as well as first hospitalization for HF. Quality-of-life scores were also improved over placebo. Combination therapy with hydralazine and isosorbide dinitrate is an appropriate substitute for angiotensin II antagonism... 

In patients with left ventricular dysfunction but no edema, an ACE inhibitor should be used first. Several large studies have showed clearly that ACE inhibitors are superior to both placebo and to vasodilators and must be considered, along with diuretics, as first-line therapy for chronic heart failure. However, ACE inhibitors cannot replace digoxin in patients already receiving the drug because patients withdrawn from the cardiac glycoside deteriorate while on ACE inhibitor therapy. 

Aliskiren is the most advanced of these and the first to be approved for the treatment of hypertension. In healthy subjects, aliskiren produces a dose-dependent reduction in plasma renin activity and Ang I and II and aldosterone concentrations. In patients with hypertension, many of whom have elevated plasma renin levels, aliskiren suppresses plasma renin activity and causes dose-related reductions in blood pressure similar to those produced by ACE inhibitors (Figure 17-3). The safety and tolerability of aliskiren appear to be comparable to angiotensin antagonists and placebo. 

The combination of diabetes mellitus and hypertension inexorably leads to diabetic nephropathy and is the major cause of end-stage renal failure. In numerous animal studies and in several small clinical trials, ACE inhibitors have been shown to significantly retard the loss of kidney function associated with diabetic nephropathy. A large, prospective, placebo-controlled study has clearly established that captopril slows the progression of diabetic nephropathy in patients with insulin-... 

The multiple difficulties encountered in the quantification of ACE inhibitor blood pressure effects have importantly contributed to a general improvement in the antihypertensive drug development process leading up to registration by health authorities (234, 235). Definition of the dose-range that is effective in blood pressure lowering has become more and more precise with time (236). It became obvious that a placebo-controlled investigation of the effect of ACE inhibitors on... 

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