Dilated cardiomyopathy medical therapy
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Treatment should focus on correcting the underlying cause of the cardiomyopathy when possible. Treatment is also targeted towards preventing death, and ameliorating the symptoms of heart failure. Medications that have been proven to reduce mortality in patients with systolic heart failure are; ACE inhibitors, beta blockers, angiotensin II receptor blockers, nitrates, and hydralazine. Diuretics and digoxin are used for symptom relief.
- Death from dilated cardiomyopathy is usually the result of progressive heart failure or arrhythmia.
- Treatments for dilated cardiomyopathy are targeted towards preventing death and treating symptoms of heart failure. Some medications (such as ACE inhibitors) may help achieve both goals.
- Initial treatment should focus on the underlying cause of dilated cardiomyopathy if reversible. If for example a patient has dilated cardiomyopathy and three vessel coronary artery disease then revascularization should be an initial step in treatment.
- Medications which have a proven survival benefit in systolic heart failure are ACE (angiotensin converting enzyme) inhibitors, ARBs (angiotensin II receptor blockers), beta blockers (carvedilol, bisoprolol and metoprolol succinate are the most well studied), aldosterone antagonists (in severe heart failure) and combination of long acting nitrates and hydralazine.
- Medications targeted towards symptom relief in systolic heart failure are diuretics and digoxin. Warfarin is also a medication used in systolic heart failure; the benefit of this medication is controversial.
ACE inhibitors in Dilated Cardiomoypathy
- ACE inhibitors are thought to be useful in dilated cardiomyopathy by not only causing arterial vasodilation and reduction of afterload but also by reduction in levels of angiotensin II, aldosterone, and ADH which may have deleterious remodeling effects on the heart as well as vasoconstriction.
- ACE inhibitors have been extensively studied in systolic heart failure and have been shown to reduce symptoms, slow the progression of heart failure and reduce mortality in all classes of heart failure. The most profound impact is seen in patients who are most symptomatic as well as those patients who have recently suffered a myocardial infarction.
- In addition ACE inhibitors have been shown to slow the progression of left ventricular dilation in systolic heart failure.
- The SOLVD-Prevention trial and SAVE trial both are large randomized controlled trials which evaluated patients with asymptomatic systolic heart failure. SOLVD-Prevention examined 4000 patients with an EF < 35% who were asymptomatic and randomized them to enalapril (dose 2.5-20mg daily) or placebo. After an average 3 years follow up there was a significant reduction in heart failure hospitalizations but no difference in mortality. The SAVE (Survival and Ventricular Enlargement) trial studied 2200 patients with an EF < or = to 40% within 3-14 days following an acute myocardial infarction. These patients were given either captopril or placebo and followed for an average of 3.5 years. There was a significant 25% reduction in myocardial infarction and a significant reduction in death from recurrent MI by 32% in the captopril group.
- The CONSENSUS, SOLVD-Treatment and V-HeFT II trials all examined ACE inhibitors in symptomatic patients with systolic heart failure. The CONSENSUS trial was published in 1987 and studied 250 patients with NYHA class IV heart failure. These patients were randomized to enalapril (dose 2.5mg - 40mg daily) or placebo. After an average follow up of 6 months there was a 40% reduction in mortality in the enalapril group (this persisted to 1 year, at 1 year there was a 31% reduction in mortality in the enalapril group). The reduction in mortality was attributed to a reduction in the death from progressive heart failure, not from a reduction in sudden cardiac death. SOLVD-Treatement and V-HeFT II also showed a reduction in mortality with ACE inhibitors, both of these studies evaluated mainly patients with NYHA class II or III heart failure.
- The AIRE and TRACE trials were placebo controlled randomized controlled trials which both evaluated ACE inhibitors (ramipril and trandolapril respectively) in heart failure following a myocardial infarction. Both of these studies also showed a reduction in mortality in the ACE inhibitor arm when compared to placebo. These studies evaluated patients at a minimum of 2 (AIRE) or 3 (TRACE) days following an acute MI.
- The CONSENSUS II, ISIS-4, GISSI-3 and SMILE studies all evaluated patients early (within 24 hours) following an acute myocardial infarction. All but the CONSENSUS II study showed a mortality benefit (both short and long term) in the ACE inhibitor arm when compared to placebo.
ARBs in Dilated Cardiomyopathy
- ARBs have also been extensively studied. There are at least four large trials which support the use of ARBs in systolic heart failure. These include the ELITE, ELITE II, Val-HeFT, and CHARM trials.
- The ELITE trial randomized 722 patients over the age of 65 with an EF < 40% and NYHA class II-IV heart failure to either an ACEi (captopril) or an ARB (losartan). After a follow up of 48 weeks there was no difference in the primary endpoint (persistent elevations in serum creatinine); however a secondary endpoint of mortality showed a risk reduction of 46% in the losartan group. This was further evaluated in the ELITE II trial which randomized 3150 patients similar to those in the ELITE trial and again compared captopril and losartan. After a mean follow up of 555 days there was no difference in mortality or resuscitated arrest, but losartan was "better tolerated" than captopril (captopril was most often discontinued due to ACEi related cough).
- The Val-HeFT trial was a placebo controlled RCT that evaluated studied valsartan use in 5000 patients with heart failure. There was a reduction in the combined endpoint of mortality and morbidity after a mean follow up of 23 months.
- CHARM randomized 7,600 patients to candesartan or placebo. There were 3 subgroups analyzed in this study. CHARM-Added trial showed that there was a reduction in cardiovascular mortality or CHF hospitalization in patients with systolic heart failure (EF < 40%) who were taking candesartan as well as an ACEi when compared to an ACEi alone. The CHARM Alternative subgroup showed that in ACEi intolerant patients with systolic heart failure (EF < 40%) there was a reduction in mortality or CHF hospitalization in patients taking an ARB (candesartan) when compared to placebo. The CHARM Preserved group evaluated patients with heart failure and a preserved ejection fraction and found no difference between candesartan and placebo.
- The data is very strongly in favor of using ACEi as first line medications for systolic heart failure, and the addition of ARBs may be helpful. In addition, if patients are intolerant of ACEi, there are clear benefits to using ARBs.
Beta Blockers in Dilated Cardiomyopathy
- Beta blockers have been extensively studied in systolic heart failure. Bisoprolol, metoprolol succinate and carvedilol are the most supported by data.
- The U.S. carvedilol study randomized roughly 1000 patients with an EF < 35% to either carvedilol or placebo. The study was stopped early as there was a 65% risk reduction in mortality in the carvedilol group and there was also a reduction in hospitalizations from a cardiac cause.
- The MERIT HF trial randomized 4000 patients NYHA II-IV with an EF < 40% to receive either metoprolol succinate ("Toprol XL") at doses 12.5mg daily uptitrated to 200mg daily or placebo. After a mean of 1 year follow up the study was also stopped early as there was a 34% risk reduction in mortality in the metoprolol succinate group. This reduction in mortality was attributed both to a reduction in sudden cardiac death as well as death from heart failure.
- Other large trials of beta blockers in systolic heart failure include CIBIS-II, COPERNICUS, and COMET.
Aldosterone Antagonists in Dilated Cardiomyopathy
- Aldosterone antagonists have been used in systolic heart failure and have been shown to have a mortality benefit.
- Based on the results of the RALES trial aldosterone antagonists are used in patients with systolic dysfunction and NYHA class III or IV heart failure. Hyperkalemia is an important side effect in heart failure patients especially who may have concominant renal disease or may be on an ACE inhibitor and / or an ARB.
- Spironolactone and epleronone are commonly used aldosterone antagonists. Epleronone is more specific to the mineralocorticoid receptors and spironolactone binds relatively more androgen and progesterone receptos; therefore, spironolactone is more likely to cause endocrine side effects such as gynecomastia in men.
- The RALES trial randomized 1663 patients with an EF < 35% and severe heart failure to spironolactone (25mg daily) or placebo. The patients were also taking ACEi, loop diuretics and most were taking digoxin. The study was stopped early after a mean of 24 months follow up as there was a 30% risk reduction in mortality noted in the spironolactone group. This reduction in mortality was attributed both to a reduction of progressive heart failure deaths and a reduction in sudden cardiac death.
Long-acting Nitrate and Hydralazine Combinations in Dilated Cardiomyopathy
- VHeFT-I and VHeFT-II have shown that there is a benefit in morbidity and mortality to long acting nitrates combined with hydralazine in patients with systolic heart failure. This effect is thought to be less robust than ACEi (VHeFT-I compared this combination to an ACEi enalapril and showed a reduction in mortality in the ACEi group). Common practice is to use this combination in patients who are unable to tolerate an ACEi or ARB; such as patients with advanced renal disease.
Warfarin in Dilated Cardiomyopathy
- As stated above warfarin is a medication that is occasionally used in systolic heart failure and the benefits are controversial. In systolic heart failure and atrial fibrillation there is a more clear benefit in terms of stroke prevention; however, in isolated systolic heart failure the reduction in embolic risk has not been fully elucidated.
Diuretics in Dilated Cardiomyopathy
- Loop diuretic medications are commonly used for patients with symptoms of heart failure. There has been no clear survival benefit associated with loop diuretics; however, the use of diuretics and a sodium restricted diet are the mainstays of treatment for congestive symptoms.
Digoxin in Dilated Cardiomyopathy
- Digoxin is sometimes used in systolic heart failure for symptom relief. A survival benefit has not been shown with digoxin use; however, it is useful for symptomatic treatment. There may be more of a role for digoxin in systolic heart failure and atrial fibrillation as digoxin may serve a dual purpose of heart failure symptom relief related to increased ionotropy as well as ventricular rate control related to AV nodal blockade.
- The RADIANCE trial and The Digoxin Study evaluated digoxin in heart failure patients.
N-3 polyunsaturated Fatty Acids
- N-3 polyunsaturated fatty acids have also been evaluated by the GISSI-HF group and showed a slight reduction in mortality (from 29% to 27%) at roughly 3 years of follow up.
- In patients with end stage heart failure or hemodynamic compromise, vasopressor agents may be helpful. In patients with hemodynamic compromise medications such as dobutamine or dopamine may provide necessary blood pressure support.
- In addition, parental agents such as milrinone (a phosphodiesterase inhibitor- somewhat specific for cardiac and vascular tissue) may be helpful in the short term or for end stage patients. There is no clear survival benefit and most trials with IV phosphodiesterase inhibitors are small trials of end stage heart failure patients. Oral milrinone has been studied and has been shown to increase mortality (as seen in the PROMISE trial).
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