Paclitaxel/Pimecrolimus

A review.Heart failure (HF) is a disabling disease with increasing prevalence and a poor prognosis despite advances in drug and device-based therapies.The biochem. rationale for using coenzyme Q10 (CoQ₁₀) in HF is correction of a deficiency state whose association with the disease was established years ago.New clin. data are promising, with CoQ₁₀ supplementation as a potential approach to improve HF outcome by impeding the vicious metabolic cycle in chronic HF.¹ Randomized controlled trials with CoQ₁₀ in HF Standard treatments of HF may have side effects, and they are administered to block neurohormonal responses rather than to support cellular bioenergetics of the failing heart.Also, these drugs do not substitute for micronutrients such as CoQ₁₀, which is why the possible deficiencies of these factors remain and contribute to symptoms and reduced survival in HF.CoQ₁₀ is a vital electron and proton carrier supporting ATP synthesis in the inner mitochondrial membrane (Figure 1) and is also a powerful lipid-soluble antioxidant.A decrease in CoQ₁₀ in myocardial tissue has been demonstrated in patients with various cardiomyopathies, and the myocardial tissue level of CoQ₁₀ was found to be inversely related to the severity of HF.² Low plasma CoQ₁₀ was found to be an independent predictor of mortality of HF patients in a cohort study from New Zealand in 2008, but this was not replicated in a prespecified substudy of the randomized controlled trial (RCT) of rosuvastatin in HF (the CORONA Trial).A recent Japanese cohort study of 276 patients admitted to the coronary care unit was presented in abstract form at the American Heart Association meeting in 2013.The authors found a correlation between low serum CoQ₁₀ levels and the risk of cardiogenic shock and in-hospital mortality, suggesting that CoQ₁₀ levels might be used to identify high-risk patients admitted with HF.International clin. data on the effectiveness and safety of CoQ₁₀ to treat patients with HF have accumulated over nearly 40 years.Open-label studies in the 1980s showed that CoQ₁₀ as adjunctive therapy with digitalis and diuretics resulted in clin. improvement after 4-12 wk of supplementation, without evidence of toxicity.³ Emphasis should be placed on the 20 RCTs published with CoQ₁₀ supplementation in HF from 1985 to 2014.The majority of these trials were smaller (fewer than 80 patients), but two larger multicenter studies have also been reported: a 1993 Italian study and the 2013 Q-SYMBIO study.^4,5 In an overview from 2003, 10 out of 13 RCTs showed improvements in various clin. parameters, including New York Heart Association (NYHA) classification, exercise capacity, and quality of life after supplementation with CoQ₁₀ (reference 3) .These results were paralleled in some, but not all, of the studies by amelioration in objective parameters of cardiac function.Three of the 13 studies, comprising <10% of the total number of patients included in RCTs, reported neither benefit nor harm from CoQ₁₀.Only two RCTs were designed to address major clin. end points.In five meta-analyses of RCTs, significant pos. effects from CoQ₁₀ supplementation or trends toward efficacy have been found with respect to either increased left ventricular ejection fraction or improvement in NYHA classification (Table 1).^6,7,8,9,10 Two of these meta-analyses showed either a nonsignificant trend toward reduced mortality¹⁰ or no effect of CoQ₁₀ on mortality.⁹ With respect to the Italian RCT, 641 patients were randomized to either CoQ₁₀ 50 mg two or three times daily (according to body weight) or placebo for 1 yr.Significantly fewer patients were readmitted as a result of worsening HF in the CoQ₁₀ group, and fewer patients died in the CoQ₁₀ group (N = 16) compared with the placebo group (N = 21), but this was not statistically significant.⁴ The preliminary results of the Q-SYMBIO study were presented at the European Society of Cardiol. Meeting, Heart Failure 2013.⁵ The data showed that CoQ₁₀ supplementation with 100 mg three times daily vs. placebo in 420 patients receiving standard therapy improved symptoms and survival, and the results have been accepted for publication in JACC: Heart Failure.The pos. outcome may reflect the increased daily dosage and the formulation of CoQ₁₀ that was used in Q-SYMBIO relative to those used in previous studies.These initiatives may be required to reach the therapeutic threshold of CoQ₁₀ supplementation in HF.An unmet need in the treatment of HF is an effective and safe pos. inotrope.Previous results from RCTs with pos. inotropic drugs have been neg., and these agents do not have a role in the oral management of HF today.According to the present US and European guidelines, digoxin is the only known pos. inotrope that may be considered, because it does not increase mortality but provides a relative risk reduction for hospital admissions for worsening HF.However, digoxin has a limited margin of safety. coq₁₀ is safe and may be described as an indirect pos. inotrope by virtue of its restoration of energy production in the mitochondria, leading to improved myocardial performance and outcome in HF.CoQ₁₀ and international guidelines for treatment in HF The pros, cons, and perspectives on the use of CoQ₁₀ are summarized in Table 1.Few topics in cardiol. are more controversial than the use of nutritional supplements in the prevention and treatment of disease.However, in the 2013 guideline for management of HF from the American College of Cardiol. (ACC)/American Heart Association (AHA), we see an endorsement of nutritional supplements, in that omega-3 polyunsaturated fatty acids were found reasonable to use as adjunctive therapy in HF based on the available evidence from RCTs.In the previous ACC/AHA HF guideline (issued in 2005), CoQ₁₀ was acknowledged to have a possible effect in some studies, but because the benefits were not recorded uniformly it was decided that CoQ₁₀ would not be recommended until more data were available.HMG CoA reductase inhibitors (statins) appear to lower blood levels of CoQ₁₀ in a dose-dependent manner via inhibition of the mevalonate pathway.The 2013 ACC/AHA guidelines on treatment of blood cholesterol to reduce atherosclerosis make no recommendation regarding initiation or continuation of statin therapy in patients with NYHA class II-IV HF.This decision is based on the results from two RCTs with statins in HF, in which pos. long-term outcomes were expected but the studies came out neutral.The possible explanations for the results are not addressed in the report.¹¹ At least theor., CoQ₁₀ depletion via statins may be critical, especially in patients with HF who have preexisting CoQ₁₀ deficiency,² and this may have contributed to the neutral outcomes of these RCTs.Statins have been associated with a variety of myopathic complaints, and the hypothesis is that statin-induced CoQ₁₀ deficiency is involved in the pathogenesis of statin myopathy.Although the hypothesis was not confirmed in a systematic review,¹² preliminary studies have shown improvements in pain scores after taking CoQ₁₀.It therefore seems reasonable to test CoQ₁₀ supplementation in patients with myalgia, if other causes of muscle pain are excluded.The question is whether the pos. outcome of Q-SYMBIO with a cohort of 420 patients will be guideline-changing evidence or whether it will be determined that a confirmatory trial is necessary.An example of a considerably smaller guideline-changing RCT is the 1987 Consensus I Trial of enalapril,¹³ which comprised only 253 patients yet changed clin. practice with the use of angiotensin-converting enzyme inhibition in HF.It seems reasonable to consider including CoQ₁₀ therapy in future HF guidelines, given that it is safe, improves symptoms, and reduces major adverse cardiovascular events.Tentatively, according to the predefined scales of the ACC/AHA HF guideline, the class of recommendation for using CoQ₁₀ could be Class IIa with a Level of Evidence B.The improved outcome from CoQ₁₀ supplementation in HF is very encouraging, and metabolic modulation of bioenergetics may be the next frontier in HF therapy.