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Heart Failure 

When one sees a patient who appears to be affected by congestive heart failure, itís very important to take the first step to defining that, in fact, congestive heart failure does exist. There are therapies that can markedly change the outcome but without appropriate recognition, weíre not able to use those therapies. So that if you were to look through any of the treatment guidelines proposed by any of the national or international associations, you would find some very simple concepts that seem obvious that I wouldnít be surprised to see form the basis of questions on a standard medicine review board.

So a presenting symptom could be something as simple as fatigue in an older person Ė shortness of breath in someone when they exert themselves Ė and itís our responsibility not to ascribe that merely to old age but to ask more questions and determine whether further workup is warranted.

ACE inhibitors, as Iíll show you, are useful across the entire spectrum of disease and beta blockers are useful up to the Class IV heart failure patient. I leave this as a gap because beta blockers have not been investigated in this population. Think of this graphic as an example of how the disease is a progressive one.

One way you could model the disease is in this fashion where you talk about a myocardial injury, the decreased contractility, neurohormones are activated to try to maintain organ perfusion causing peripheral vasoconstriction and thereís a feedback loop that causes basically the cycle to progress and amplify, neurohormones cause progressive ventricular dysfunction and it leads to this critical syndrome.

Now one of the things thatís very interesting about this disease is that it would seem as though we have three perfectly useful targets to try to interrupt this cycle, to change the natural history and, in fact, weíve all learned about the ability to increase contractility, to give vasodilators as well as adrenergic antagonists that all seem to make sense. But one cannot rely purely on that kind of common sense to make decisions. If one were to look at the literature of the long term effects Ė remember this is a long term chronic disease, not just acute exacerbation Ė of positive inotropes, there are two studies in particular which shed led on the utility of this strategy.

One was a study using intermittent intravenous dobutamine or placebo in patients with heart failure that came in, had a dobutamine effusion for 24 hours, one day a week and were followed prospectively to see what their outcomes were. This study, although it was presented back in 1986, had a database that was buried by the sponsor who in fact stopped the study early because of what they noticed to be a significant problem.

But it was corroborated by another positive inotropic agent, norinol, which was initially developed as an oral agent. Itís currently available as an intravenous one. This study had 1100 patients enrolled with Class III to IV heart failure and found that even though this drug can acutely improve filling pressures, acutely improve contractility and even make patients feel better for the first few weeks and improve their exercise tolerance.

In fact, when one looks through this database you find that itís not as simple as a tradeoff between feeling better and potentially dying early. These drugs do not provide us that tradeoff even if we wanted to utilize it. Essentially, the patients may have felt better by some subjective measures in the first couple of weeks, but really there was no clinical benefit at any time during treatment.

Itís important to emphasize the fact that even though I may be giving you the message that hydralazine and Isordil arenít useful for heart failure, that if you were to look through treatment guidelines which have a slightly lower hurdle that needs to be achieved to consider a drug useful, they often include hydralazine and nitrates as alternative therapy in patients who are symptomatic despite optimal therapy.

In terms of the way somebody would probably write a word question, the perception you should have is that they are considered to be useful but as second line therapy even through the randomized control trials do not conclusively show that they favorably effect long term outcome.

In contrast to the disappointing results with inotropes and vasodilators are the results with neurohormonal antagonists. There are abundant studies showing that neurohormonal activation occurs in proportion to symptomatic and hemodynamic severity of disease as well as correlate with long term outcomes. For example, if one were to look at plasma renin activity in patients not treated with an ACE inhibitor, one would see that the group in red, representing those with the greatest activation, had the highest risk of death over five years with those in green with the least activation having the lowest risk of death. This has been corroborated by other databases.

So itís not surprising to us that if we look at the clinical trials databases of ACE inhibitors that ACE inhibitors beat placebo across the disease spectrum irrespective of which ACE inhibitor weíre talking about. So Iíve summarized the survival curves from three landmark studies. SAVE looked at patients post myocardial infarction with no evidence of heart failure symptoms but with low ejection fraction. Captopril 50mg three times a day in red, significantly better than placebo.

SOLVE treatment trial will take patients with Class II to III heart failure, mild to moderate heart failure, and now will titrate it towards a target of 10 mg twice daily, significantly better in red than the placebo group in yellow. Then the CONSENSUS trial which looked at severe Class IV patients, Vasotec titrated with a target dose of 20 mg twice daily, a very high dose, showed such a significant benefit shown in red that the study was stopped

I grew to think that this was a useless drug. It was associated with a lot of hyperkalemia when you got up to those dosage levels that you needed to to get good diuresis when you were adding it to an ACE inhibitor and yet Aldactone has some very interesting effects because one of the things it does is it blocks aldosterone and it can block aldosterone at a fairly low dose. So that the RALF study, on the basis of several smaller pilot studies that were used for dose finding, utilized a dose primarily of 25 mg once daily of Aldactone with the hypothesis that that wouldnít be enough to cause much in the way of hyperkalemia or diuresis but could antagonize aldosterone. Aldosterone has many proven effects on the heart to cause it to remodel, to cause it to become fibrosed, to alter its geometry, to assume a less favorable geometric status.

So this study enrolled about 1600 patients. The followup was two years and it was stopped early because they initially reported a mortality reduction of 27%. It was reported in the New England Journal web site about two weeks ago and it will be coming out in print in the next month or so and the final numbers show risk reduction of 29% with a very small P value. This is a very compelling piece of information. Very strong data that fits in with our model. Itís clinically relevant in its difference and everyone in the heart failure community, I think, buys into this as saying that patients with Class III or IV failure or who have been hospitalized within the last six months Ė those are the entry criteria Ė should be started on Aldactone at this low dose. They should be monitored for hyperkalemia because it is possible but really the focus should be on getting patients on this drug as much as possible.

Iíd like to touch briefly on angiotensin receptor blockers. Thereís been a lot of attention focused on ELITE which looked at both losartan versus captopril and was touted as showing that losartan was better. It was touted as showing losartan was better because of this line showing the P value was less than 45 favoring losartan. I would like to point out that this was a secondary analysis of a study that was not designed to show this that did not adjust for multiple looks at the data or multiple secondary endpoints. If you were to do that, which any regulatory authority or treatment guidelines would want to do at least to some extent, this is not a statistically significant finding. ELITE II is trying to address whether, in fact, there is a difference and itís in the followup phase and probably will be reported in the next six months.

Itís important not to necessarily use ARBs even though they make sense because there is still some conflicting data of their utility. The RESOLVE study looked at 769 patients with the drug canazart compared to enalapril or its combination. When this study was finishing, there was some controversy as to whether or not canazart may have been associated with a worse outcome, either alone or in combination. Essentially, the Safety Monitoring Board was thinking of stopping the study but the study was almost over and they waited for a little more data and the trends are going in the wrong direction although they are not statistically significant. But it should be a study that raises enough concerns about ARBs that you donít necessarily utilize them instead of ACE inhibitors unless you are certain the patient canít tolerate an ACE inhibitor. Certainly on a board review question, ARBs are not considered standard therapy for heart failure.

Iíd like to turn to the sympathetic nervous system because this is another neurohormonal system whose activation correlates with disease severity. Weíre talking the sympathetic nervous system as not a system that we should antagonize in heart failure because youíll see things like this that show that when you take patients with heart failure, have them on a constant sodium balanced diet, theyíre at relative rest so negative sodium balance, you start them on propranolol, they shift to sodium retention, thatís not good. If you were to look at what happens to ejection fraction measured by echo after a day of even a low dose of mitopavol, you could find data that show this. That after one day, thereís a small but significant reduction in ejection fraction consistent with the data that we know that shows that beta blockers are negative inotropes and thatís true. The pharmacologic effect is that they are negative inotropic and thatís a problem when youíre giving it to someone with a low ejection fraction.

But if you were to look at what happens in patients in whom we start out with a low dose, cautiously up-titrate towards target, make sure youíve treated them with appropriate background therapy and see what happens during long term therapy, youíll see this kind of graph. I showed you

How can this be? Well, what happens is that over time, beta blockers produce a positive inotropic shift. They change the biology of myocardium. So they have initial pharmacologic effect and then a positive biologic effect. These are data from desindilol which will not be marketed but this is an early study within heart failure patients looking at intraventricular manometry Ė a very precise way to measure contractility showing an increase in systolic elastic Ė very accurate measures of contractility Ė and this has been shown in two other beta blockers also.

The basis for this has been demonstrated in myocardium taken from patients with heart failure before and after therapy by endomyocardial biopsy. What Iíd like you to focus is on the left side, the patients with idiopathic dilated cardiomyopathy had a relative paucity of the alpha myosin heavy chain which hopefully all of us have a dominance of in this room which is the faster, more powerful myosin isoform. The beta functions well in an energy depleted environment. If you look at the right panel and look at the red group, youíll see that the responders are the ones whose alpha myosin heavy chain increased over time so that there does appear to be a data supporting that there is a biological shift that occurs after, in this case, six months of therapy.

If one were to look at the clinical trials data, you could find a bunch of studies with different beta blockers all showing benefit. Iíll briefly run through some of the data. This is with carbanalol with mild heart failure showing significant and clinically relevant reduction in risk. This was verified by a longer term study in Australia, New Zealand with carbanalol. Again, a significant reduction in risk.

This is associated with an increased ejection fraction. This is data from the U.S. carbanalol trials. Mild heart failure and moderate heart failure so you can expect a 7-8 point increase in ejection fraction after six to twelve months of therapy.

These are data from the SIVIS trial which was recently published in Lancet about almost eight months ago showing bisoprolol, a beta-1 selective agent. Also a significant and clinically relevant reduction in risk. So another beta blocker that works.

These are preliminary results that have subsequently been published with tocolactol showing "all cause" mortality reduced 32%, hospitalizations reduced about the same amount.

So if we look at the totality of data with beta blockers, we see thereís even more patient studies with beta blockers  than with ACE inhibitors. The same kinds of findings. The mortality reduction of 32%, the risk of hospitalization, death 37% are facts shown in patients already receiving ACE inhibitors. So these are additional facts and as far as your pharmacology lectures and medicos telling you that polypharmacy is not good, in heart

There are some unanswered questions. I talked about these before. We donít know about the safety or efficacy in patients who have Class IV heart failure with beta blockers being studied now. We donít know about the patients with Class I heart failure although there are some circumstantial data from the post MI trials. We donít know if all beta blockers are created equally. Thereís a study ongoing comparing pritopolol to carbanalol in

We talked about a number of targets. Hemodynamic targets are not useful for the treatment of chronic heart failure. The renin-angiotensin aldosterone system is an important target as is the sympathetic nervous system. Iíll touch briefly on some of the other targets that are being explored and the feeling of potent vasoconstrictors, cytokines with tumor necrosis factor that you probably heard about from the oncologist but itís probably more relevant here and in rheumatoid arthritis and perhaps weíll mention the cardiac matrix as well as the 

In terms of cytokines, there are a variety that have been shown to be activated. The best described is tumor necrosis factor. Tumor necrosis factor is an agent that is seen at very high levels at end stage heart failure where patients are cachectic. It also appears to be released earlier in the disease process as well and itís on that basis that a number of basic studies and early clinical trials were initiated that have led to a Phase III study that is currently under way, about the last three months, looking at a TNF versus acetyl TNF receptor antibody. One thatís actually already on the market for rheumatoid arthritis Ė tenorcift Ė as a treatment for these patients with chronic heart failure so that as I said, there are these pathological effects,

Iíve tried to summarize that here where rats had TNF pumps implanted and so they infused tumor necrosis factor alpha and one saw that there was progressive remodeling over the first week, fraction was shortly reduced. One dose of this binding antibody was given at day 7 with a halting of this progressive dilatation and a reversal in the systolic dysfunction. This kind of finding, a reversal of systolic dysfunction with a single dose has been