Faith and nesiritide: "The substance of things hoped for. The evidence of things not seen."

I had one of those clinics and I never billed anyone a cent for my contribution. My secondary gain was just the satisfaction that my patients seemed to feel better, and in the several months I ran it, it was a very rewarding experience. It was a small gathering of patients, never more than three or four at a time who shared a penchant for breathing, or more correctly, a penchant for avoiding drowning. Their least favorite hangout was the local hospital, requiring admission every two to six weeks, and they could rarely make it three months without lugging all their pill bottles and their worn-out luggage over to the step-down unit for admission. They were "The Natrecor Gang," and they were a rowdy geriatric bunch that shared a zest for life, galvanized by the fact that they were dying of congestive heart failure. They mourned the clinic closing and asked me the same question every time I would see them: "Are 'they' ever going to let us take that medication again?" ASCEND-HF likely answered that question today with a resounding "No!"

I'm not in any way refuting the outcome of the ASCEND-HF trial. It was a beautifully designed trial that gave this compound every opportunity to show itself in a positive light, but nesiritide failed. What I do insist on is that we should come away with a lot more than what the primary end point demonstrated. There is much more to this story than creatinine and mortality data. There is a very human element that should prompt us to examine not only why it didn't work in the trialists' eyes, but why it did work in the eyes of the patients who took it and in the opinion of many physicians who administered it.

One of my first outpatients was a spry 80- something- year- old who sat home during her STEMI and suffered from what she thought was a shortage of "Tums" and other antacids. She finally agreed to come for admission when she could no longer breathe enough to lie flat. She presented with an EF of about 28% with one of those echos where the proximal segments are all racing hard, galloping like a horse on Derby day, the apex dyskinetic and dead weight to the rest of its mother ventricle. She was "cold and wet," with BPs too low for much of anything, but responded to a little dobutamine, a smidgen of carvedilol, and eventually a little ultralow-dose ACE inhibitor. She limped home after about a week but returned again a month later with rales to her scapulae. Her viability study was a disappointment, of course, and she had no reversible ischemia in her other segments. After a healthy chastisement regarding fluid and sodium restriction, I enlisted the help of our home health agency to ensure patient compliance. That lasted about three months, and then she was back again. It was during the "heyday" of nesiritide so I tried it one admission and she diuresed with almost instant improvement. Outpatient clinics were up and coming and growing in popularity. Seeing how she loathed the inpatient setting, I thought I'd give it a try. She was our first enrollee.

My second patient was a woman with severe diastolic dysfunction. She had a thick stiff heart muscle and about 30 pounds of fluid she carried begrudgingly from the knee to the ankle. Her BUN was 50 and her creatinine ran about 1.8. Any increase in the other "unproven therapy" of furosemide just led to a higher BUN. She slept in a chair or on four pillows at home every night as she had done for a couple of years. After several admissions, I offered her a spot in the outpatient clinic, and she didn't even hesitate. I tried her in the inpatient setting on nesiritide, and her BUN held up well despite a "several-liter" diuresis. We joked that we were "going to get those legs ready for a summertime bikini," and her eyes sparkled.

The third patient was a mixture somewhat of patient number one and patient number two. She had significant diastolic dysfunction, mild reduction in LVEF, probably from poorly controlled intermittent afib I later discovered. It was during an inpatient admission that she finally revealed her "dark secret" of a 180-bpm-rate intermittent atrial fib. She'd had undergone three "normal" coronary angiograms in a 10-year period. She, too would come frequently for admission for treatment of her "big legs" and shortness of breath, and she too would diurese with natrecor, once to the point that her creatinine elevated significantly, so I had to hydrate her back moderately, but her creatinine completely recovered. I learned at that point not to be greedy with nesiritide.

These patients and the rest of the "gang" met up in the outpatient IV therapy room on the fourth floor of our hospital. They were lovingly attended by our IV therapy nurses who got to know them, called to check on them at home, went over their medications, and called me frequently to come see them. They were all started on twice-weekly infusions but then all eventually were able to cut down to weekly appearances. Their hospital admissions were cut dramatically. Their demeanor improved, and their quality of life seemed good for them again. Over the course of that year, one of them did have a couple of admissions, but that was nothing compared with her previous course. They were devastated when we had to close. I still used nesiritide frequently in the inpatient setting for a while, but eventually, from fear of safety and litigation, I stopped using it altogether.

When it's all said and done, I still think nesiritide or the principles and theories on which it was developed has a place in medicine, but I agree that we do not currently understand exactly when or how the synthetic analogs of human BNP will find their place in heart-failure therapy. I never believed that careful nesiritide titration would cause renal failure. I'd seen far worse things happen to patients with plain old well-accepted Lasix on a fairly regular basis, but nonetheless, the question of safety was raised by those far more educated than myself on the topic, so we all had to defer, and rightly so.

I wonder whether we should do a trial of renal-perfusion dopamine simultaneously with nesiritide in order to blunt the hypotension (and yes, renal-perfusion dopamine does indeed "press" the occasional patient). I wonder if the real answer is that these patients simply cannot survive without the most intense treatment regimen known to humankind, which requires daily or thrice- or twice-weekly hands-on medical attention. I wonder if nesiritide is kind of like those benefits we see from things like massage, faith, or prayer. Folks swear by them, but we can find no objective measures at this time in human history to explain it.

Something happens to those patients, though. Rivers of beautiful crystal white urine cascade down catheter tubing as a testament to its success, and patients will tell you how much better they feel after several hours of infusion. I recall a similar thought as I reviewed the EVEREST trial, in which the regurgitant volumes were really not significantly reduced, but boy did those patients feel better.

For now, it will take more than faith to get another Natrecor infusion going in my hospital, but maybe the same faith that leads to thousands of patients receiving therapy and believing they felt better will lead to the real truth and a new therapy. For all the congestive heart-failure patients who are still suffering in the world, we can only hope it does. After suffering for so long, still all that many of those patients can cling to is their faith that something will come along sooner or later, hopefully much, much sooner.

See also:
ASCEND-HF: Nesiritide safe but of limited dyspnea benefit in acute HF

Your comments

	Faith and nesiritide: "The substance of things hoped for. The evidence of things not seen."
	# 1 of 1	December 2, 2010 04:32 (EST)
	Roby Mitchell MD	T3 will work better,is cheaper,and will improve renal function. Also,mesenchymal stem cell therapy is taking NYHA Class 4 patients off transplant list. See <www.cellmedicine.org>

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