Back to CARDIOLOGYAs we approach the 21st century, we, begginners in the medical field, have the opportunity to participate in extraordinary advances in understanding and treating diseases. Still, there are some aspects of medicine that have a long way to go, in a sense that looks like we are dealing with a new disease, something that we have never heard before. That's the case when we consider heart failure treatment, which by no means is a new disease but the drawbacks in its treatment makes it feel like we are dealing with an uncurable disease, like AIDS.
In the next three series of articles in this section, we will review carefully the current concepts in the treatment of systolic heart failure, independent of etiology; in other words, what we are doing with patients with unreversible contractile dysfunction of the myocardium. We are going to discuss the pharmacological therapy, surgical therapy and transplant therapy, respectively. In a fourth article, we will present an approach to diastolic heart failure, a completely different entity. I would appreciate to have comments and questions in my email, so that we can make a profound and rational discussion of a major public health problem.
Currently over 3 million people have heart failure in USA, with more than 400.000 new cases yearly and an annual cost of managment of aproximately US $ 10 to 15 billion. Having that diagnosis means an ominous prognosis even with all the armamentarium available today, with an annual mortality of < 5% for assymptomatic, 10 % for mild, 20 to 30 % for moderate and 30 to 80 % for severe left ventricular ( LV ) dysfunction.
What we have to keep in mind is that managment of congestive heart failure ( HF ) is no longer confined to relief of symptoms, as the process that contributes to LV dysfunction progressess independently from the development of symptoms, so that treatment aimed at symptom relief may be quite different than one aimed at preventing or delaying the progression of LV dysfunction.
The understanding of the pathophysiology of HF have changed from one that highlights a primary myocyte dysfunction ( with altered contractility ) to an altered neuro-humoral compensatory mechanism that in turn leads to altered structure and function of not only myocytes but also of intersticial myocardial cells. In that scheme, any stimulus that leads to myocardial damage and LV dysfunction ( coronary artery disease, hypertension, cardiomyopathies or valvular heart disease ) will trigger a suicidal process of compensatory mechanisms aimed at maintaining pump function.
In other words, what happens is that after an injury that leads to LV dysfunction a neuro humoral reaction takes place aimed at maintaining pump function and tissue perfusion by means of adrenergic stimulus ( maintaining blood pressure and heart rate ) and activation of the renin-angiotensin system, wich leads to myocardial hypertrophy and dilatation besides its effects in other vascular and renal territories. Innitialy this process is highly beneficial, helping the failing left ventricle in keeping with its function. Unfortunately, this is also a suicidal process in a way that it creates a vicious circle that involves left ventricular dilatation, pump dysfunction, more neuro-humoral activation that in turn leads to more ventricular remodeling and higher working loads ( because of higher afterload and wall stress ), which in turn leads to further pump dysfunction and further neuro-humoral activation, creating an endless process that ultimately leads to severe heart failure. So what we try to do is to interrupt this vicious circle with drugs that modulate the adrenergic and renin-angiotensin systems, which is a quite different concept from that old one of aiming at inotropic support to the failing heart, one that enhances the neuro-humoral activation and leads to progressive deterioration.
When treating patients with HF we have two primary objectives, one in the short term and one in the long term. In the first case, we are trying to give the patient the best quality of life possible, which means primarily relief of symptoms, allowing as normal life stile as possible. Even tough, its important to note that it does not imply better survival, which is aimed with the long term treatment.
Before proceding with the current strategies for pharmacological therapy, I have to comment on the previous belief that HF needs to be treated with drugs that provide inotropic support. Although patients do get better in terms of symptoms with this approach, all current inotropic drugs tested so far in clinical trials, with the exception of the 200 year-old digoxin which we will talk about bellow, have shown actually to INCREASE mortality. Included in this group are Dobutamine, Amrinone, Milrinone, Ibopamine, Flosequinan, Pimobendan and Vesnarinone. The last drug was initially shown to have a survival advantage in low doses while an increased mortality was seen with higher doses. This issue was settled very recently, when the Vest study, a double blind, placebo controlled, randomized trial which primary end point was mortality, presented in the European Congress of Cardiology in August this year in England, showed defitively that Vesnarinone, even in small doses also increases mortality ( data not yet published ). So if we are going to give any inotropic support, this is done in hemodynamic unstable patients and aiming only better quality of life, with exception of digoxin.
To relief symptoms, we are use nonpharmacological maneuvers, digoxin, diuretics and vasodilators. The first ones consist of restricting the salt intake to 2-3g/day (which will reduce the need for diuretics), exercicing as strenuously as symptoms permit (formal rehabilitation programs can increase peak exercice capacity, enhancing quality of life; please note that this recomendation against the previous belief that bed rest was part of HF treatment)and mechanical interventions when appropriate (PTCA, CABG, valve replacement, tranplantation).
Diuretics are used to relieve circulatory congestion and the subsequent pulmonary and peripheral edema. Importantly, in the absence of symptoms or signs of congestion, diuretics have no place in managment of HF and may induce neurohormonal activation that could have a deleterious effect. Diuretics are generally given in whatever doses are needed to relieve fluid retention, as best assessed by measuring central venous pressure ( elevated pressure in the internal jugular vein or hepatojugular reflux ). We can use either thiazides or loop diuretics, their dosage and frequency of administration varying from 2-3 times weekly to 1-2 times daily. The best approach is to teach patients to adjust their diuretic intake according to their weigh, as measured each morning, as it will vary with level of activity and diet. Excess diuresis is as harmful to a patient as inadequate diuresis, causing fatigue, hipotension and azotemia in the presence of a normal jugular venous pressure. We should also not forget to give potassium replacement when high doses of diuretics are used.
Vasodilators, by alleviating both preload and afterload, provoke an increase in stoke volume, a reduction in LV filling pressure and some relief of symptoms and improved exercice tolerance. This can be done with ACE inhibitors, hidralazine + isosorbide dinitrate or their combination. The dosages of these vasodilators are individualized on the basis of tolerance and symptoms, although the target daily doses in clinical trials are hidralazine 300 mg, isosorbide dinitrate 160 mg and Captopril 150 mg or Enalapril 20mg. These target doses are the ones shown in trials to add survival benefit beside symptom relief. Of course, they should be started in low doses and slowly titrated upward as tolerated by the patient. Actually, patients frequetly do not tolerate these high doses, as they cause hypotension and other side effects. These are target doses, as they were used in trials that evaluated their efficacy in HF. So, we use the highest dose that a particular patient tolerate, if possible trying to reach doses used in trials.
Digoxin is the oldest inotropic drug available and although cardiologists have a long experience with its use and its modulatory action on barorreceptors, its use in HF patients in sinus rhythm has long been disputed, but its benefits in patients with atrial fibrillation are well recognized. We have firm evidence that withdrawal of the drug can adversely affect symptoms ( RADIANCE trial ,NEJM 1993 ), but the long term safety of the drug has been questioned on the basis of some retrospective data showing an adverse effect on survival. The answer to these questions came early this year, when the DIG trial ( not yet published ) was presented in the American College of Cardiology meeting in Orlando, USA. This is a randomized, prospective trial that enrolled 7.788 patients with NYHA class II and III HF in sinus rythm, most of whom were already taking diuretics and ACE inhibitors. The primary end point of this study was the impact of adding digoxin to the above regimen on total mortality. Patients were divided in two groups, based on ejection fraction ( group1 - EF < 45%, group 2 - EF > 45% ), and were randomized to receive either digoxin ( 0.125-0.5 mg/day ) or placebo and were followed for 37 months. The results showed that the total mortality was exactly the same with either digoxin or placebo, independent of ejection fraction, etiology of HF, heart size or NYHA class. Even though, patients who received digoxin had less deaths due to progressive HF an due to arrhythmias. Also digoxin lead to less hospitalization and better quality of life. So, the conclusions drawn were that digoxin is not effective ( but not detrimental ) to provide a better survival but, as it gives good symptomatic relief, leads to better quality of life, less costs of hospitalizations and is the first inotropic agent that does not lead to increased mortality, we should keep using it. This was a landmark study that answered questions that were highly awaited.
Now we turn to the pharmacological approach aimed at increasing survival of HF patients, which we use beside some non pharmacological maneuvers as abstaining from alcohol in patients with alcoholic cardiomyopathy and surgical procedures for reversible causes of HF. Vasodilators are the mainstem of therapy aimed at increasing survival, as it interferes with the neuro-humoral systems that are highly active in HF, causing vasocontriction, increased afterload, LV remodeling, direct myocyte-toxic effects, arrhythmias and thromboembolic phenomena, as we discussed above. In 1986, the V-HeFT I study established the principle that medical therapy ( with Hidralazine and nitrates ) could prolong survival in patients with symptomatic HF. On the heels of that study, the CONSENSUS and SOLVD trials definitively showed that ACE inhibitors also improved survival ( by about 40 % ). V-HeFT II then compared these therapies directly and and showed that the survival benefit was greater with ACE inhibitors. Also, the SOLVD trial demonstrated a slight trend towards increased survival in assymptomatic HF patients ( EF < 0.35 ). Additional clinical and survival benefits of ACE inhibitors in trials among patients who have had myocardial infarctions have reinforced the role of these agents as a cornestone of therapy in patients with impaired ventricular function. Ideally, these drugs should be given in the dosages found in clinical trials to increase survival ( as shown above ).
Antiarrhythmic drugs are not currently recomended to supress ventricular arrhythmias except in the event of ventricular fibrillation in a patient in whom carefful monitoring ( including electrophysiologic testing ) demonstrates the effectiveness and safety of these drugs. Amiodarone is used more often than other drugs. To date, two major studies were done to adress this issue. The firt one is the GESICA trial, made in Argentina, which randomized 516 patients with nonsustained ventricular tachycardia to either amiodarone or placebo and was terminated prematurely because of a 28% risk reduction in mortality in the drug group and a slightly but nonsignificant lower rates of sudden death and death due to progressive HF. The second trial, publishe in the NEJM in 1995, is the CHF-STAT trial, which examined the effects of amiodarone in HF patients with 10 or more ventricular premature beats ( a marker of high risk for sudden death ). Unexpectedly, amiodarone had no significant effect on survival at two years. So, the issue is highly controversial and a better definition awaits futher studies that are ongoing. Even though, these two studies were reassuring about the safety profile of amiodarone. Another important issue about arrhythmic sudden death in HF patient is that its cause is bradiarrythmias in 70 % of cases, with only 30 % being due to taquiarrhythmias; this statment can explain why amiodarone and other antiarrhythmic drugs have not been shown to have a protective effect against sudden death, as they can actually promote or agravate bradiarrhythmias.
Since thromboembolism is a potential complication in HF, some experts recommend routine prophylatic anticoagulation. Although no prospective trial of anticoagulation has been conducted in such patients, retrospective data indicate that the risks are so low ( 2-3 per 100 patient-years ) that the rationale for routine anticoagulation is questionable. Those patients at particulat high risk for thromboembolism ( with atrial fibrillation, a history of embolism ) should probably receive indefinively anticoagulant therapy. Aspirin is frequently used as a substitute of warfarin, but recent concepts about interference with the action of ACE inhibitors made its use questionable ( remember that the converting enzime also is responsible for degradation of bradikinin, a prostaglandin that may be the most important effector of the beneficial effect of ACE inhibition, so that when we give ACE inhibitors we are elevating the levels of bradikinin ). There are some recent studies that show that if we inhibit the effects of bradikin we abolish the effects of ACE inhibitors.
Despite this achievements, the rates of morbidity and mortality from HF remain high, and new therapeutic strategies are needed. Evidence has been accumulating to support an entirely different approach to treatment og HF - one of using beta blockers. The importance of the adrenergic system in supporting the failing heart has long been known, making inhibition of this system appear counterintuitive. However, after reports from Sweden of clinical benefits, the concept have emerged that sustained activation of the adrenergic nervous system in HF is counterproductive and that the gradual administration of beta blockers could interrupt that vicious circle that leads to in an inexorable way to pump dysfunction and death. Many trials have shown hemodynamic benefits ( with Metoprolol and Bisoprolol ) but no survival benefit; that was until May this year, when a randomized trial of Carvedilol ( a nonselective beta blocker that also blocks alfa 1 receptors and, unlike other beta blockers, has antioxidant effects that may be important in HF ) was publised in the NEJM. This study enrolled 1094 patients with chronic HF receveing diuretics , ACE inhibitors and digoxin, that were randomized to either carvedilol or placebo. After a 65 % reduction in the risk of death was shown the trial was terminated prematurely. Carvedilol also lead to a 27 % reduction in hospitalizations for cardiovascular causes. Although this is only the result of a single, definitive trial with adequate power to detect changes in the mortality, the experince with carvedilol is very promising, even though there are some drawbacks in this studies. Carvedilol should be use in doses from 6.25 to 100 mg daily. It should be started very carefully, ideally in highly supervisionized patients ( if possible hospitalized ) and the doses should be titrated upward very slowly. Patients can get worse of HF symptoms initially, but after some time the ejection fraction goes up and they get better. We should avoid using it in class IV patients; they should be treated with other means until they go to class III and then started on beta blockers cautiously. Cardiologists need to get used to what Oncologists face everyday : when first treating cancer with chemotherapy, patients feel awfull and after some time they get better. That's a concept in which we have to accept an innitial worsening to have a good long term effect to our patients. Its quite different from the old one that aimed at immediately releiving symptoms but not worring about the future, and we now know that the prognosis in this patients is not good.
Finnaly, I would like to comment on terminal patients for whom no form of alternative therapy is available ( surgery, transplant,... ). In this group the prognosis is dismal ( 50-80 % 1year mortality ), so that we need to give them the best quality of life possible, assuming our incapacity to cure this syndrome. In this group we should give inotropic support either orally or intravenously so that they can get ride of their congestive symptoms and live the best possible life they can, even though we know that we are possibly making them dye a bit earlier ( ? ). Its our obligation as physicians to alleviate pain and other symptoms of those unfortunate patients for whom science has not yet found a cure.
So, we conclude by saying that surely the future is promisig for HF treatment, with molecular biology techniches offering the hope for curing and preventing a variety of diseases. I encourage readers to discuss with me this very important theme, making questions and comments and saying about your experience in Cardiology by my email. I also would like to hear comments about the format of writting, if it is suitable for those who read it and consequently making the objective of informal talking and learning with people all over the world via the net.
- Current Opinion in Cardiology - Cardiac Failure/Cardiomyopathies Vol 11 No 3 May 1996
- New England Journal of Medicine, May 23 1996 ( Carvedilol study )
- NEJM, July 13 1995 ( CHF-STAT Amiodarone study )
- NEJM, August 15 1996 ( Review of Managment of HF )
- NEJM, 1993, 329:51-53 ( Editorial - Digixin in HF )
- NEJM, 1993, 329(1):1-7 ( Withdraw of Dogoxin in HF )
- NEJM, 1992, 327:669-77 ( ACE inhibitors after myocardial infarction )
- NEJM, 1992, 327:685-691 ( SOLVD trial )
- Circulation, 1993, 87( Supp VI ) VI32-VI39 ( VHEFT II trial )
- J am Coll Cardiol , 1992, 19:842-50 ( Vasodilators in HF )
- Lancet, 1994, 344:493-498 ( Amiodarone in HF )
- NEJM, 1993, 329:149-55 ( Vesnarinone in HF )
Back to CARDIOLOGY
Back to SPECIALTIES
Back to MEDSTUDENTS HOMEPAGE