Presenter: Barry M Massie, MD (University of California, San Francisco VA Medical Center, San Francisco, California)

Approximately 50% of heart failure patients have a normal or near-normal left ventricular (LV) ejection fraction ("heart failure with preserved systolic function"), and it has been found that morbidity and mortality are as high in this group as they are in heart failure patients with low ejection fractions. Few clinical trials have been carried out in these patients, however, mainly because of difficulties in recruiting the older, predominantly female patients. This difficulty was recently highlighted by the Perindopril for Elderly People with Chronic Heart Failure (PEP-CHF) trial,^[1] which fell short of its intended enrollment of 1000 heart failure patients without major LV systolic dysfunction, even with an extended period of recruitment. Trials in these patients also tend to have high drop-out rates and follow-up may be limited. Both PEP-CHF and the other, larger trial carried out in patients with preserved LV systolic function, the Candesartan in Heart Failure--Assessment of Mortality and morbidity (CHARM)-Preserved trial,^[2] failed to meet their primary endpoints, attributed by the respective lead investigators to the short follow-up duration.

I-PRESERVE

The largest ongoing trial in heart failure with preserved LV systolic function is the Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) trial, a phase 3, randomized, double-blind, placebo-controlled study investigating the benefits of the angiotensin receptor blocker (ARB) irbesartan (target dose 300 mg/day) in patients with preserved ejection fraction.^[3] The study is funded by Bristol-Myers Squibb (Princeton, New Jersey) and sanofi-aventis (France). Patient recruitment has been completed and the I-PRESERVE investigators believe that they have succeeded in enrolling a population similar to that in epidemiology studies, with a predominance of older patients and women with underlying hypertension and relative infrequent coronary artery disease (CAD).^[4] Their study population also differs substantially from the CHARM-Preserved patients, more closely resembling those in the community, the I-PRESERVE investigators say. This may influence the outcome of the trial, and the application of its results, they believe.

Patient Recruitment

I-PRESERVE recruited patients who fulfilled the following inclusion criteria:

• Symptomatic heart failure (New York Heart Association [NYHA] class II-IV)
  
  
• Left ventricular ejection fraction (LVEF) ≥ 45%
  
  
• Age ≥ 60 years
  
  
• Hospitalization for heart failure within 6 months or corroborative evidence of heart failure or cardiac substrate for LV dysfunction from electrocardiogram (ECG), echocardiogram, or chest x-ray

Patients were excluded from the trial if they had any of the following:

• Any prior ejection fraction < 40%
  
  
• Primary valvular disease, restrictive or hypertrophic obstructive cardiomyopathy, cor pulmonale, pericardial disease, uncontrolled angina, or uncontrolled arrhythmia
  
  
• Confounding conditions such as severe chronic obstructive pulmonary disease (COPD), anemia, or severe hypoalbuminemia
  
  
• Myocardial infarction, stroke, or revascularization procedure within 3 months
  
  
• Significantly high or low blood pressure (systolic blood pressure [SBP] > 160 mm Hg or < 100 mm Hg)
  
  
• Serum creatinine > 2.5 mg/dL (221 mmol/L) or other major laboratory abnormality
  
  
• Other conditions that might limit life expectancy or interfere with adherence to the protocol

After a 2-week single-blind run-in period, patients were randomized in a 1:1 ratio to receive either irbesartan, titrated from 75 mg to 300 mg as tolerated, or placebo, and were stratified by site and baseline angiotensin-converting enzyme (ACE) inhibitor use.

The primary endpoint is a composite of all-cause mortality or protocol-specified cardiovascular hospitalizations for nonfatal myocardial infarction (MI), stroke, heart failure, unstable angina, or dysrhythmia. Secondary endpoints include:

• Cardiovascular death
  
  
• Major cardiovascular events (cardiovascular death, nonfatal MI, or nonfatal stroke)
  
  
• Heart failure endpoint (heart failure mortality or heart failure hospitalization)
  
  
• Change in NYHA functional class
  
  
• Global change score
  
  
• Quality of life (Minnesota Living With Heart Failure questionnaire)
  
  
• Change in brain natriuretic peptide (BNP)

Two substudies are being carried out at selected sites. An echocardiographic substudy is assessing a number of parameters associated with diastolic function to determine whether treatment with irbesartan results in improvement in the left atrial area, and the other substudy is examining collagen markers associated with heart failure in these patients.

Study Population

Beginning June 2002, patients were enrolled into the trial at 293 sites in 24 countries including the United States, Mexico, and Canada, Western and Eastern Europe, Australia, and South Africa. Enrollment was completed in 2005 at a total of 4128 patients. All patients were symptomatic and 44% had been hospitalized for heart failure within 6 months. Most patients had underlying evidence of left ventricular hypertrophy (LVH) on echocardiogram and/or ECG or left atrial enlargement (86% with echo LVH or left atrial enlargement and 31% with ECG LVH), and 40% had pulmonary congestion on x-ray.

Level of BNP was not an entry criterion for the study, since information about BNP in diastolic heart failure is limited, Dr. Massie explained. The study did aim to obtain BNP measurements in all patients at baseline and at 2 points of follow-up, but in the end, baseline BNP values have been obtained from only 3400 patients. In these patients, BNP measured at a core laboratory using the Roche N-terminal (NT)-proBNP assay was elevated (mean 864 ? 1723 pg/mL), consistent with heart failure diagnosis. Additional BNP data may be obtained at a later date, Dr. Massie said.

Follow-up is planned to continue until 1440 patients experience a primary endpoint. Dr. Massie, who is cochair of I-PRESERVE, explained that the trial was originally designed for 3600 patients, but as that number approached, 2 months behind schedule, the investigators found that the event rate was far lower than had been projected on the sample size. With the option of either following the 3600 patients for a longer time or enrolling more patients, the investigators chose to do both, insofar as possible. Thus, patient enrollment was increased to 4100, and the target number of events should occur in the third quarter of 2007, Dr. Massie predicted. "Average follow-up, which was planned to be 3 years, is going to be closer to 4 years," he said. "The downside is that more people will discontinue therapy. We lose about 6% per year who go off drug. That is fairly typical for a trial, but now we have added a year, there is a chance that we may lose more."

Comparison With CHARM-Preserved

The I-PRESERVE investigators say that the patients enrolled in the trial are similar to those in epidemiologic studies in most respects, including mean age (72 years) and percentage of women (60%) (Table 1).^[5-9] Mean ejection fraction in the I-PRESERVE population is 58.4%. A history of hypertension, present in the majority of patients (88%), was considered to be the primary etiology of heart failure in most patients (63%) compared with only 25% considered to have heart failure of ischemic etiology. Few of the patients had prior MIs (23%) or had undergone coronary revascularization (13%).

Table 1. I-PRESERVE Patient Characteristics Compared With Data Collated From Epidemiology and Cohort Studies and From CHARM-Preserved

	I-PRESERVE	Cohort and Epidemiologic Studies	CHARM- Preserved
Mean age (yrs)	72	75	67
Women	60%	65-70%	40%
Ejection fraction	59%	60%	54%
Primary cause of heart failure:
Hypertension	63%	60%	23%
CAD	25%	25%	56%
History of hypertension	88%	80-90%	63%
History of MI	23%	<20%	45%
Prior CABG/PCI	13%	<20%	39%
Stroke/TIA	10%	NA	9%
Atrial fibrillation	29%	20-30%	29%
Diabetes	27%	20-30%	29%

CABG = coronary artery bypass graft; CAD = coronary artery disease; MI = myocardial infarction; PCI = percutaneous coronary intervention; TIA = transient ischemic attack.

The baseline characteristics of the I-PRESERVE patients differed substantially from those in the CHARM-Preserved study, which randomized 3023 patients with chronic heart failure and preserved LV ejection fraction (> 40%) to treatment with the ARB candesartan, starting at 8 mg /day titrated to 32 mg/day, or placebo.^[10] The I-PRESERVE patients were older than the CHARM-Preserved patients (72 vs 67 years, respectively), the proportion of women was higher (60% vs 40%), more had hypertension as a cause of heart failure (63% vs 23%), and CAD was less frequent (25% vs 56%).

Both the I-PRESERVE and CHARM-Preserved populations were well treated with antihypertensive agents (diuretics, beta-blockers, spironolactone, and calcium channel blockers, but not ACE inhibitors, because they were limited by protocol) and agents often used for low ejection fraction heart failure (Table 2).

Table 2. I-PRESERVE: Baseline Medications

	I-PRESERVE	CHARM- Preserved
ACE inhibitors (%)	25	19
Beta-blockers (%)	59	56
Diuretics (%)	83	75
Spironolactone (%)	15	12
CCBs (%)	40	31
Digoxin	14%	28%
Aspirin	54%	58%

ACE = angiotensin converting enzyme; CCB = calcium channel blocker.

"The big difference from CHARM-Preserved is that the CHARM investigators were really looking at people with ejection fraction ≤ 40% and putting all the others [with ejection fraction > 40%] into the CHARM-Preserved study," Dr. Massie noted. "It was a great thing to do, but it was not really designed specifically to look at this group," he said.

Dr. Massie explained that the reason the I-PRESERVE investigators decided to enroll patients based on evidence of normal or new-normal ("preserved") ejection fraction is that "it implies the minimum about the pathophysiology" of the patients' condition. Little is known about the pathophysiology of preserved systolic function and there is no simple and straightforward diagnostic test, he noted. "Ejection fraction is not systolic function," he said. "You can have a normal ejection fraction and have systolic dysfunction, and almost everybody who is in that middle range also has some degree of systolic dysfunction." Most of the I-PRESERVE patients did not have major diastolic dysfunction, he added.

It should be recalled that the CHARM-Preserved arm failed to meet its primary endpoint. After a median follow-up of 36.6 months, candesartan was associated with a trend toward a reduction in cardiovascular mortality or hospital admissions for CHF. Although there was no difference in cardiovascular deaths, significantly fewer candesartan-treated patients were hospitalized for CHF compared with the placebo group. At the time the results were presented, CHARM investigator Salim Yusuf, MB MS, DPhil (McMaster University, Hamilton, Ontario, Canada), suggested that longer follow-up may have been needed for the full effects of candesartan to emerge in this population. The I-PRESERVE investigators predict that they will not have this problem.

TOPCAT

An even larger study in heart failure patients with preserved systolic function is scheduled to begin recruitment shortly. Funded by the US National Heart, Lung and Blood Institute (NHLBI), the Treatment Of Preserved Cardiac function heart failure with an Aldosterone anTagonist (TOPCAT) trial will examine the effects of aldosterone antagonist therapy (spironolactone 15 mg) vs placebo in 4500 adult patients with heart failure. Patients will be enrolled on the basis of an echocardiographically assessed ejection fraction. They will be recruited over a 2.5-year period, treated, and followed for a minimum of 2 years. Approximately 250 clinical centers are expected to participate in TOPCAT, which investigators anticipate will be completed in 2011.

References

1. Cleland JG. The Perindopril for Elderly People with Chronic Heart Failure (PEP-CHF) study. Presented at the World Congress of Cardiology 2006; September 2-6, 2006; Barcelona, Spain. Hot Line Session I, September 3, 2006.
2. Yusuf S, Pfeffer MA, Swedberg K, et al; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362:777-781.  
3. Carson P, Massie BM, McKelvie R, et al; for the I-PRESERVE Investigators. The irbesartan in heart failure with preserved systolic function (I-PRESERVE) trial: rationale and design. J Card Fail. 2005;11:576-585.  
4. Massie B, Carson P, Komajda M, et al. The baseline characteristics of patients enrolled in the irbesartan in heart failure with preserved systolic function trial are similar to those in the community but differ from CHARM-Preserved. J Card Fail. 2006;12(6 suppl 1):S77.  248.
5. Hogg K, Swedberg K, McMurray J. Heart failure with preserved left ventricular systolic function: epidemiology, clinical characteristics, and prognosis. J Am Coll Cardiol. 2004;43:317-327.  
6. Vasan RS, Benjamin EJ, Levy D. Prevalence, clinical features and prognosis of diastolic heart failure: an epidemiologic perspective. J Am Coll Cardiol. 1995;26:1565-1574.  
7. Masoudi FA, Havranek EP, Smith G. Gender, age, and heart failure with preserved left ventricular systolic function. J Am Coll Cardiol. 2003;41:217-223.  
8. Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006;355:260-269.  
9. Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355:251-259.  
10. McMurray J, Ostergren J, Pfeffer M, et al; CHARM committees and investigators. Clinical features and contemporary management of patients with low and preserved ejection fraction heart failure: baseline characteristics of patients in Candesartan in Heart Failure--Assessment of Mortality and morbidity (CHARM) programme. Eur J Heart Fail. 2003;5:261-270.

Presenter: Rajesh K C Vindhya, MD (Columbia University College of Physicians & Surgeons, New York, NY)

Three concepts have emerged recently as possibly essential to understanding important aspects of cardiovascular disease (CVD): phenotype (particularly as it pertains to hypertension), metabolic syndrome (particularly as it pertains to CVD risk), and preserved ejection fraction (particularly for a significant proportion of heart failure patients). Now a study reported at the 2006 Heart Failure Society of America conference has found that among elderly patients with heart failure with preserved ejection fraction, the metabolic syndrome is more often found in those with hypertension than those without hypertension. However, the study found no difference in cardiovascular structure and phenotype between these 2 groups.^[1]

The question thus becomes, What is intrinsic to this condition, and what is an incidental aspect of the presentation? How should researchers identify the patients to be studied?

As explained by Rajesh Vindhya, MD: "Obesity, such a common problem in the United States, has been associated with myocardial infarction and coronary artery disease, but it has not been associated with heart failure. So we conducted our research not only with the hope of trying to show an association between obesity and heart failure, but taking the whole metabolic syndrome into account."

The Logic of the Question

Heart failure with normal or preserved ejection fraction, which is subsumed under the umbrella term diastolic heart failure, is unlike true diastolic heart failure, where the problem is intrinsic, Dr. Vindhya explained. In heart failure with preserved ejection fraction, extracardiac factors such as anemia, renal dysfunction, and obesity play a major role. "Since metabolic syndrome is also an extracardiac factor, it makes sense to try and associate it with diastolic heart failure," Dr. Vindhya said.

Subjects with metabolic syndrome have been reported to have higher left ventricular (LV) mass and more concentric LV hypertrophy, as indicated by higher relative wall thickness. This cardiovascular phenotype is often thought to characterize patients with heart failure in the setting of a preserved ejection fraction.

Hypertension is also commonly associated with heart failure with preserved ejection fraction. Dr. Vindhya and his colleagues therefore investigated the presence of the metabolic syndrome in a cohort of subjects with heart failure with preserved ejection fraction who were sorted according to the presence or absence of hypertension and stratified by the presence or absence of the metabolic syndrome.

Subjects

The study involved 71 subjects, all of whom had been diagnosed with heart failure with preserved ejection fraction. Consistent with previous studies, all subjects were required to meet the European Society of Cardiology criteria for diastolic heart failure^[2]:

• Signs and symptoms of congestive heart failure;
  
  
• Normal or at most mildly reduced LV ejection fraction (≥ 45%); and
  
  
• Evidence of abnormal diastolic function on standard Doppler echocardiographic evaluation of transmitral inflow patterns.

Of the 71 subjects, 46 had clinical hypertension. The 25 patients without hypertension included 4 patients with cardiac amyloid, 7 with hypertrophic cardiomyopathy, 10 with hemochromatosis, and 4 with a restrictive cardiomyopathy. Compared with the hypertensive patients, those without hypertension tended to be older (mean age 71 years vs 44 years), female (80% vs 60% in the hypertensive group), and heavier (mean body mass index [BMI] 32 vs 27 kg/m²).

Metabolic Syndrome

Only 8% of the 25 patients without hypertension were identified as having the metabolic syndrome. Among 46 subjects with hypertension, 28 (61%) met criteria for the metabolic syndrome, defined as presence of ≥3 of the following criteria:

• Hypertension;
  
  
• Diabetes mellitus;
  
  
• Obesity (BMI > 30);
  
  
• Triglycerides > 150 mg/dL [1.69 mmol/L]); or
  
  
• HDL-cholesterol < 40 mg/dL (1.04 mmol/L).

There was no difference in age, gender, or race between subjects with or without the metabolic syndrome.

Cardiac Structure and Function/Arterial Properties

In the hypertensive patients, LV volumes and mass were evaluated by freehand 3-dimensional echocardiography, and large conduit artery stiffness was identified by pulse pressure. No differences were seen in cardiac structure, function, or arterial properties between subjects with or without the metabolic syndrome among these hypertensive subjects (Table 1).

Table 1. Cardiac Structure and Function in Hypertensive Subjects

Parameter	Metabolic Syndrome (n = 28)	No Metabolic Syndrome (n = 18)
LV size:
LVIDd (cm)	4.6 ? 0.7	4.6 ? 0.6
IVSd (cm)	3.14 ? 0.75	3.33 ? 0.4
EDV (mL)	120 ? 28	116 ? 33
ESV (mL)	56 ? 15	56 ? 16
Myocardial characteristics:
PWT (cm)	1.3 ? 0.3	1.3 ? 0.4
LV mass (g)	175 ? 37	175 ? 59
RWT (cm)	0.59 ? 0.18	0.53 ? 0.16
EDV/mass ratio	0.70 ? 0.18	0.68 ? 0.13
End systolic stress (g/cm2)	115 ? 49	146 ? 55
LV function
Ejection fraction (%)	53 ? 5	52 ? 3
Stroke volume (mL)	62 ? 16	61 ? 18
Arterial properties:
Pulse pressure (mm Hg)	58 ? 17	64 ? 22
Pulse pressure/stroke volume (mm Hg/mL)	1.0 ? 0.3	1.2 ? 0.6
Arterial elastance (mm Hg/mL)	1.7 ? 0.4	2.1 ? 0.7

EDV = end-diastolic volume; ESV = end-systolic volume; IVSd = interventricular septum thickness during systole; LV = left ventricular; LVIDd = LV internal diameter during diastole; PWT = posterior wall thickness; RWT =relative wall thickness.

Blood Volume Analysis

Measurements of total blood volume, red cell volume, and plasma volume in a subset of 22 patients (15 with metabolic syndrome and 7 without) were similar in the 2 groups (Table 2).

Table 2. Blood Volume Analysis

Parameter	Metabolic Syndrome (n = 15)	No Metabolic Syndrome (n = 7)
BV (cc)	4630 ? 1000	3031 ? 1549
PV (cc)	3194 ?799	3396 ? 1022
RCV (cc)	1432 ? 244	1635 ? 600
BV/BSA (cm/m2)	2388 ? 314	2572 ? 574
PV/BSA (cm/m2)	1642 ? 254	1734 ? 356
RCV/BSA (cm/m2)	744 ? 97	838 ? 262

BSA = body surface area; BV = blood volume; PV = plasma volume; RCV = red cell volume.

Conclusions

Among the patients with preserved ejection fraction, no significant differences were found between those with and without metabolic syndrome; however, the concomitant prevalence of both conditions is so high that the conclusion of Dr. Vindhya and his colleagues is that further studies are definitely warranted to define the mechanistic interaction of these 2 syndromes.

References

1. Vindhya RKC, Wajahat R, Titova I, et al. The metabolic syndrome in patients with heart failure with normal ejection fraction. J Cardiac Fail. 2006;12(6 suppl):S20.  065.
2. The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005). Eur Heart J. 2005;26:1115-1140.

Presenter: Katherine Lietz, MD, PhD (Cardiovascular and Cardiothoracic Divisions, University of Minnesota, Minneapolis)

Since the approval of the first left ventricular assist device (LVAD) as "destination therapy" in patients with end-stage heart failure in the United States in November 2002, many patients who were deemed ineligible for heart transplantation have received LVADs as an alternative permanent solution. However, the in-hospital mortality rate in these patients could be reduced if patients are referred for destination therapy before major complications and comorbidities develop, investigators from leading US destination therapy centers say. Now they have developed a preoperative risk score for survival to hospital discharge after LVAD implantation, which allows prospective stratification of destination therapy candidates, identifying the patients most likely to benefit from LVAD implementation and avoiding "futile" implants.^[1]

According to their study, the primary risk factors for poor outcomes appear to be poor right ventricular function, end-organ dysfunction, and general bad medical condition and poor nutrition at the time of implantation.

Calculation of the risk score was done using data from patients implanted with the HeartMate SNAP-VE (Sutures Not APplied-Vented Electric) LVAD (Thoratec, Pleasanton, California) in the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial, which first reported in 2001 that implantation of LVADs could be used as an alternative to heart transplantation,^[2] augmented with data from patients who have received second-generation LVADs. The study on which the score was based was a collaboration by the 5 largest destination therapy centers in the United States: University of Minnesota, LDS Hospital, Salt Lake City, Utah; Advocate Christ Medical Center, Oak Lawn, Illinois; Duke University Medical Center, Durham North Carolina; and Columbia-Presbyterian Medical Center, New York.

REMATCH

The REMATCH trial was carried out in 129 patients with end-stage heart failure, ineligible for heart transplantation because of age (> 65 years) or the presence of diabetes mellitus with end-organ damage, chronic renal failure, or other clinically significant conditions. The use of an LVAD in 68 patients was compared with optimal medical management (digoxin, diuretics, angiotensin-converting enzyme inhibitors, and beta-blockers, in conjunction with controlled diet and exercise managed by heart failure specialists) in 61 patients. The HeartMate SNAP-VE was already approved and in use as a bridge to heart transplantation.

All patients had symptoms of New York Heart Association (NYHA) class IV heart failure. The group that received LVADs showed a significant reduction of 48% in the risk of death from any cause compared with the optimum medical management group (relative risk, 0.52; 95% confidence interval [CI], 0.34-0.78; P = .001). The rates of survival at 1 year were 52% in the LVAD group and 25% in the optimum medical management group (P = .002), and the rates at 2 years were 23% and 8% (P = .09), respectively.

Most of the LVAD patients who died during the first year after implantation developed serious postoperative complications, had prolonged duration of hospitalization (mean 88 days vs 44 days in the optimal medical management group), and the majority died in hospital prior to hospital discharge.

REMATCH vs Post REMATCH

Approval of the HeartMate SNAP-VE device as destination therapy by the Food and Drug Administration (FDA) in the United States was based on the REMATCH trial results, published in 2001.^[2] In April 2003, the HeartMate eXtended Lead Vented Electric (XVE) LVAD, an enhanced version of the HeartMate SNAP-VE, was also approved for use as destination therapy. Changes in the new device were designed to ease implantation, provide for longer and more reliable device life, and improve patient outcomes.

By December 1, 2005, 311 patients had been implanted with the HeartMate XVE as destination therapy at 65 US hospitals. Dr. Lietz and her colleagues compared data from follow-up through January 20, 2006 in 258 of these patients with data from the 68 patients who had received LVADs in REMATCH (the post-REMATCH group). Data on the patients in the post-REMATCH group were obtained from the FDA-mandated Destination Therapy Registry maintained by Thoratec. All patients fulfilled Centers for Medicare & Medicaid Services (CMS) criteria for destination therapy:

• NYHA class IV heart failure symptoms
  
  
• Maximized medical therapy for heart failure for ≥ 60 of the past 90 days
  
  
• Life expectancy < 2 years
  
  
• Not a candidate for cardiac transplantation

The characteristics of the 2 patient groups were similar (Table 1). The post REMATCH patients were severely ill, with only 21% able to undergo cardiopulmonary testing. Most had > 1 contraindication for cardiac transplantation, including advanced age, renal dysfunction, and/or severe pulmonary hypertension, and most had ≥ 1 contraindication for enrollment in the original REMATCH trial.

Table 1. Recipients of Destination Therapy

Patient Characteristics	Post REMATCH (n = 258)	REMATCH (n = 68)
Male	87%	78%
Mean age (yrs)	61 ? 12	66 ? 9
Ischemic heart failure	67%	78%
% LVEF	17 ? 6	17 ? 5
Systolic blood pressure	102 ? 15	101 ? 15
Cardiac index	2.0 ? 0.7	1.9 ? 1.0
Intravenous inotropes	68%	65%
No ACE inhibitor/ARB	38%	38%
Beta-blockers	57%	24%
Cardiopulmonary test	21%	-

Median follow-up in the post REMATCH patients was 15 months and median discharge time was 5 weeks. During support time, the condition of 32 patients (13%) improved and they underwent heart transplantation. In the remainder, survival at 1 year was 57%, at 2 years was 38%, and there was approximately 14% perioperative mortality.

Early mortality rates showed no significant improvement with the new over the old LVAD, Dr. Lietz noted. Of the 101 deaths during the first year after LVAD implantation, 67 (67%) occurred prior to hospital discharge. In-hospital mortality associated with destination therapy was 26.4%. The main causes were similar to those seen in the REMATCH trial, ie, sepsis, multiorgan failure, and right heart failure (Table 2).

Table 2. Causes of Death in the Post REMATCH Group

Cause of Death	In-hospital (258 patients [%])	After Discharge (183 patients [%])
Sepsis	8.9	7.1
Multiorgan failure	5.4	1.6
Right heart failure	3.5	0.5
Stroke	0.4	4.4
LVAD failure	1.1	2.7
Hemorrhage	0.8	0.5
Other	5.4	11.5

Risk Factor Analysis

The investigators examined a range of preoperative risk factors to identify patients who would be at excessive operative risk for implantation of an LVAD. They looked at 61 preoperative factors, including:

• Medical history
  
  
• Functional capacity
  
  
• Patient demographics
  
  
• Preoperative medical/device therapy
  
  
• Laboratory parameters
  
  
• Vital signs and hemodynamics

Univariate analysis showed that survival until hospital discharge after LVAD implantation was largely determined by 3 major factors:

• Right ventricular function
  
  
• End-organ function
  
  
• Nutrition and general medical condition

Surprisingly, Dr. Lietz reported, no association was found between outcome and LV function, measured as systolic blood pressure, diastolic blood pressure, cardiac output/cardiac index, pulmonary capillary wedge pressure, systemic vascular resistance, and LV ejection fraction. They also found that patients with no requirement for inotropic therapy had an increased risk of complications, that there was a weak trend toward poor outcomes in patients intolerant to ACE inhibitors/angiotensin receptor blockers (ARBs) or beta-blockers, and that patients with arrhythmias were at increased risk.

These findings were confirmed by multivariate analysis of markers of right ventricular function, liver function, and renal function (Table 3). In addition, Dr. Lietz explained, hematologic abnormalities such as anemia and coagulopathy were associated with increased risk of transfusions and bleeding, markers of infection or inflammation revealed patients at increased risk of developing sepsis, and small recipient size (body surface area, body mass index, and weight) and low albumin levels were also predictors of poor outcome.

Table 3. Preoperative Predictors of In-hospital Death (multivariate analysis; n = 205)

Risk Factor	Risk Ratio	95% CI	P Value	Weight
PLT ≤ 148 x 10/mcL	10.3	3.3-32.8	< .001	9.5
BSA ≤ 1.9 m2	8.2	2.2-29.5	< .001	7
Serum creatinine clearance < 30 mL/min	7.7	1.5-38.7	< .1	6.5
WBC >12 x 10/mcL	6.5	1.7-24.6	< .001	5.5
mPAP ≤ 25.3 mm Hg	5.9	1.8-18.7	< .001	5
Vasodilatory therapy	5.8	1.5-14.7	< .001	5
History of arrhythmias	5.5	1.0-20.3	< .1	4.5
INR > 1.1	4.6	1.1-18.7	< .1	3.5
Albumin ≤ 3.3 g/dL	3.6	1.2-10.2	< .1	2.5
Hct < 34.5%	2.7	0.9-8.0	< .1	2.5
ALT > 90 or AST > 90 U/dL	2.6	0.9-6.8	< .1	1.5
No intravenous inotropes	2.4	0.9-6.8	< .1	1.5
No beta-blockers	2.2	0.9-5.8	< .1	1

ALT = alanine aminotransferase; AST = aspartate aminotransferase; BSA = body surface area; Hct = hematocrit; INR = international normalized ratio; mPAP = mean pulmonary arterial pressure; PLT = platelets; WBC = white blood cell count.

There was no association between outcome and site of implantation, year, or implanting center size, although there was evidence of an increased risk associated with the first 5 LVADs implanted vs the following 5 LVADs at any given center. The impact of proper patient selection was overwhelming overall, however, and more important than the experience effect, Dr. Lietz stressed. No correlation with risk was found for prior sternotomy, prior myocardial infarction, or prior coronary artery bypass graft.

Application of Risk Score

Based on a weighted scale, a score was calculated for each risk factor and then a risk score was calculated for each patient prior to surgery. When patients were stratified by "preoperative cumulative risk for in-hospital mortality" into low (n = 21), medium (n = 127), high (n = 22), and very high (n = 38) risk (total 205), the investigators found that as heart failure worsened, corresponding survival to hospital discharge after LVAD implantation decreased progressively from 100% to 70%, 52%, and 16%, respectively (Figure). One-year survival decreased from 94% to 74%, 31%, and 8%, respectively.

Figure. Survival with destination therapy by preoperative risk in post REMATCH patients (n = 205).

Dr. Lietz explained that as heart failure progresses, with worsening of nutritional state and right ventricular and end-organ function, the operative risk of LVAD implantation increases, and at some point these implants are futile, as in the high-risk post-REMATCH patients. This group showed a 1-year survival of only 8%, which was less than the 1-year survival rate (25%) in the optimal medical treatment group in the REMATCH trial, she pointed out. The remaining post REMATCH patients had acceptable preoperative risk, with 1-year survival of 71% and 2-year survival of 50%.

Dr. Lietz stressed that the key to survival after destination therapy is to identify the right time, ie, the "perfect window," for LVAD implantation. This scoring system is not a perfect model, and because of the small patient numbers used to develop it, it will take 2 to 3 years to validate, she noted. However, "we now have some information on what leads to poor outcomes," she said, and she urged her fellow surgeons to apply this knowledge, even before the risk score has been validated. "We need to validate the scoring system, but it is imperative to understand the mechanisms that lead to patients' mortality through LVAD implementation," she concluded.

References

1. Lietz K, Long J, Kfoury AG, et al. Risk score to predict survival to hospital discharge after left-ventricular assist device (LVAD) implantation as destination therapy (DT). J Card Fail. 2006;12(suppl 1):S4.  010.
2. Rose EA, Geijns AC, Moskowitz LJ, et al; the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med. 2001;345:1435-1443.

Presenter: Akshay S Desai, MD, MPH (Brigham & Women's Hospital, Boston, Massachusetts)

An analysis of patients who participated in the Atrial fibrillation Clopidogrel Trial with Irbesartan for the prevention of Vascular Events (ACTIVE) program has added support for the use of aspirin in heart failure patients on angiotensin converting enzyme (ACE) inhibitor therapy.^[1] In over 2000 patients with a history of heart failure and atrial fibrillation, there was no evidence of aspirin-related attenuation of ACE inhibitor benefit, Dr. Desai reported.

Since the first reports from the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II)^[2] and Studies of Left Ventricular Dysfunction (SOLVD),^[3] suggesting that the effect of ACE inhibitors was attenuated in coronary heart disease patients who were taking aspirin, reports published in the medical literature have both supported and contradicted the possibility of an interaction between aspirin and ACE inhibitors. Some studies have suggested that aspirin therapy may attenuate the benefit of ACE inhibitors in heart failure survival. Others have found that aspirin does not negatively affect heart failure survival when combined with ACE inhibitors. It has been suggested that the use of different aspirin dosages in the studies may have led to the conflicting results.

A recently published observational study in over 7000 patients from 103 Canadian hospitals concluded that aspirin use was not associated with an increase in mortality rates or heart failure readmission rates, and aspirin did not attenuate the benefits of ACE inhibitors, even in patients without coronary disease, patients with renal dysfunction, or patients treated with high-dose aspirin and low-dose ACE inhibitors.^[4]

The most reliable way to determine the answer to this question, investigators agree, would be by testing the hypothesis in a randomized, controlled trial using a 2-by-2 factorial design, but such a trial is unlikely ever to be done for ethical reasons. However, 2 randomized trials have been attempted, the results of which raised concerns about aspirin, although both trials were underpowered. The Warfarin/Aspirin Study in Heart failure (WASH) showed trends toward worse outcomes and a significantly higher risk of heart failure hospitalization in the aspirin group compared with the placebo or warfarin group.^[5] In the Warfarin and Antiplatelet Therapy in Chronic Heart Failure Trial (WATCH), the risk of heart failure hospitalization was higher in patients treated with aspirin compared with those treated with warfarin or clopidogrel. However, heart failure hospitalization was a secondary outcome in both trials.^[6]

It was in this context that Dr. Desai and the other ACTIVE investigators analyzed data from the ACTIVE-W trial, in which patients were randomized to clopidogrel plus aspirin or oral anticoagulation therapy with warfarin, to determine whether any interaction between aspirin and ACE inhibitors was present in the approximately 2000 patients with heart failure.

ACTIVE Program

The ongoing ACTIVE program consists of 3 separate interrelated trials.^[7] Patients eligible for and willing to take oral anticoagulation therapy were enrolled into ACTIVE W, and patients with a contraindication to or who were unwilling to take oral anticoagulation therapy were enrolled into ACTIVE A, in which clopidogrel was compared with placebo in patients receiving aspirin. The third trial, ACTIVE I, was a randomized placebo-controlled trial of the angiotensin receptor blocker (ARB) irbesartan for eligible patients from either ACTIVE A or ACTIVE W.

Patients were eligible for the ACTIVE program if they had electrocardiographic evidence of atrial fibrillation and ≥1 of the following risk factors:

• Age ≥ 75 years;
  
  
• Current treatment for systemic hypertension;
  
  
• Previous stroke, transient ischemic attack, or non-CNS systemic embolus;
  
  
• Left ventricular dysfunction with left ventricular ejection fraction < 45%;
  
  
• Peripheral arterial disease; or
  
  
• Age 55-74 years with either diabetes mellitus requiring drug therapy or previous coronary artery disease (CAD).

ACTIVE W

A total of 6706 patients were recruited into ACTIVE W and randomly allocated to receive oral anticoagulation therapy with warfarin (target international normalized ratio of 2?0-3?0; n = 3371) or clopidogrel (75 mg/day) plus aspirin (75-100 mg/day recommended; n = 3335). The goal of ACTIVE W was to establish that clopidogrel plus aspirin is statistically noninferior to oral anticoagulation therapy. The primary endpoint was first occurrence of stroke, non-CNS systemic embolus, myocardial infarction (MI), or vascular death. Analyses were by intention-to-treat.

ACTIVE W was stopped early because of clear evidence of superiority of oral anticoagulation therapy. There were 165 primary events in patients on warfarin (annual risk 3.93%) compared with 234 in those on clopidogrel plus aspirin (annual risk 5.60%), for a relative risk of 1.44 (95% confidence interval [CI] 1.18-1.76; P = .0003).^[8] This finding was driven largely by higher rates of stroke and non-CNS systemic embolus with clopidogrel plus aspirin. Patients who were already on oral anticoagulation therapy at the time of study entry and were randomized to warfarin had less bleeding than if randomized to clopidogrel plus aspirin. By contrast, patients not already on oral anticoagulation therapy at enrollment who were then randomized to warfarin treatment had more bleeding than those randomized to clopidogrel plus aspirin. The investigators concluded that, on the basis of these findings, warfarin was clearly a better treatment than clopidogrel plus aspirin in this population.

Almost one third of the ACTIVE W patients (2031) had an investigator-reported history of heart failure. At baseline, patients with a history of heart failure were likely to be hypertensive or diabetic, have LV dysfunction, and have prior MI or coronary disease. Heart failure patients were more likely to be treated with an ACE inhibitor or ARB.

The patients with a history of heart failure were almost twice as likely to experience a primary endpoint than those without a history of heart failure (Table 1). However, there was no significant difference in the relative benefit of warfarin over dual antiplatelet strategy with regard to prevention of thromboembolic events (P interaction, .53). Within the heart failure subset, there was no difference in bleeding complications between warfarin- and aspirin-treated patients.

Table 1. Primary Endpoint (Stroke, Non-CNS Systemic Embolism, MI, or Vascular Death) Stratified by Heart Failure History

Patient Subset	Clopidogrel + Aspirin (Rate/100 pt-y)	Warfarin (Rate/100 pt-y)	RR	95% CI
All patients (N = 6706)	3.93	5.60	1.44	1.18-1.76
No history of heart failure (n = 4675)	4.39	2.86	1.56	1.19-2.06
History of heart failure (n = 2031)	8.50	6.33	1.38	1.03-1.84

CI = confidence interval; CNS = central nervous system; MI = myocardial infarction; pt-y = patient-years; RR = relative risk..

Death or Hospitalization for Heart Failure

In the main trial, in contrast to the primary endpoint, there was no difference between the 2 treatment groups with regard to the rate of heart failure hospitalization or death (Table 2). The patients with a history of heart failure were almost 3 times more likely to experience heart failure hospitalization or death than those with no history of heart failure, but within both patient groups there was no difference in this endpoint between the 2 treatments (P interaction, .88).

Table 2. Heart Failure Hospitalization or Death

Patient Subset	Clopidogrel + Aspirin (Rate/100 pt-y)	Warfarin (Rate/100 pt-y)	RR	95% CI
All patients (N = 6706)	7.56	7.07	1.07	0.92-1.26
No history of heart failure (n = 4675)	4.60	4.27	1.08	0.85-1.38
History of heart failure (n = 2031)	14.55	13.28	1.11	0.90-1.36

CI = confidence interval; pt-y = patient-years; RR = relative risk.

There was no benefit with warfarin and no statistically significant interaction, suggesting no measurable variation in the benefit of aspirin therapy with regard to background ACE inhibitor use (P interaction, .79) (Table 3).

Table 3. Heart Failure Patients: Death or HF Hospitalization by ACE Inhibitor Use

	Clopidogrel + Aspirin		Warfarin
	N/n	Rate/100 pt-y	n/N	Rate/100 pt-y
No ACE inhibitor	54/314 (17.2%)	13.37	51/315 (16.2%)	13.02
ACE inhibitor	126/677 (28.6%)	15.18	121/725	13.40
Overall	180/991 18.2%		172/1040 (16.5%)

ACE = angiotensin converting enzyme; HF = heart failure; pt-y = patient-years.

Similar results were found when the analysis was repeated, excluding the patients randomized to warfarin who were on aspirin at baseline, again indicating no significant aspirin-ACE inhibitor interaction. This was not changed by analysis of individual components of the primary endpoint (Table 4).

Table 4. Heart Failure Patients: Other Outcomes by ACE Inhibitor Use

	Clopidogrel + Aspirin		Warfarin		P Interaction
	N/n	%	n/N	%
CHF hospitalization:
No ACE inhibitor	34/314	10.8	30/315	9.5	.096
ACE inhibitor	86/677	12.7	83/725	11.4
Death:
No ACE inhibitor	29/314	9.2	32/315	10.2	.63
ACE inhibitor	59/677	8.7	60/725	8.2
CHF hospitalization, MI, vascular death:
No ACE inhibitor	57/314	18.2	51/315	16.2	.90
ACE inhibitor	132/677	19.5	121/725	16.7

ACE = angiotensin converting enzyme inhibitor; CHF = congestive heart failure; MI = myocardial infarction..

Limitations of the Analysis

As with previous, similar, nonprespecified analyses, this study was subject to limitations. The most important was that there was no randomization to ACE inhibitor in ACTIVE W. Other limitations included the low aspirin dose used (75-100 mg), investigator-reported diagnosis of heart failure, the broad spectrum of LV ejection fraction in the heart failure patients, and possible confounding by clopidogrel use and ARB randomization in the ACTIVE I study.

Future of the Debate

Writing in a recently published editorial about the possibility of an aspirin-ACE inhibitor interaction in Circulation,^[9] Pardeep Jhund, MB ChB, and John J V McMurray, MD (Western Infirmary, Scotland, UK), lamented that the only available data were from "unsatisfactory" exploratory analyses in small prospective randomized trials with limited numbers of events and large observational studies and retrospective subgroup analyses.

An ongoing double-blind, randomized clinical study, the Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial, is comparing the relative effectiveness of these drugs in preventing death or stroke in patients with heart failure. Funded by the National Institute of Neurological Disorders and Stroke (NINDS), WARCEF has a target enrollment of 2860 patients. It is designed to test the primary null hypothesis of no difference between warfarin (INR 2.5-3) and aspirin (325 mg) on 3- to 5-year event-free survival for the composite endpoint of death or stroke among patients with ejection fraction ≤ 35% without atrial fibrillation or mechanical prosthetic heart valves.^[10] Drs. Jhund and McMurray have not given up hope of a placebo-controlled clinical trial, however. "If we can test a statin in placebo-controlled trials in patients with heart failure and coronary heart disease, perhaps we should reconsider doing the same for aspirin," they wrote.

Current Recommendations

Current national and international guidelines differ about use of aspirin in heart failure patients. The European Society of Cardiology guidelines^[11] recommend against aspirin: "Aspirin should be avoided in patients with recurrent hospitalization with worsening heart failure (Class of recommendation IIb, level of evidence B)."

The guidelines of the American College of Cardiology/American Heart Association (ACC/AHA)^[12] regard the issue as more open, saying that "There may be an important interaction between aspirin and ACE inhibitors, but there is controversy regarding this point, and it requires further study."

The Heart Failure Society of America (HFSA) Comprehensive Practice Guidelines^[13] recommend aspirin for certain patients only: "Aspirin is recommended in most patients [with ischemic cardiomyopathy] for whom anticoagulation is not specifically indicated. [However,] routine use of aspirin is not recommended in patients with heart failure not from ischemic cardiomyopathy and without other evidence of atherosclerosis vascular disease. . . . Aspirin and an ACE inhibitor in combination may be considered for patients with heart failure where an indication for both drugs exists."

References

1. Desai AS, Healey JS, Pfeffer MA, et al; for the ACTIVE Investigators. Aspirin and the risk of heart failure hospitalization in patients with atrial fibrillation and a prior history of heart failure: an ACTIVE-W analysis. Presented at the 10th Annual Scientific Meeting of the Heart Failure Society of America; September 10-13, 2006; Seattle, Washington.
2. Nguyen KN, Aursnes I, Kjekshus J. Interaction between enalapril and aspirin on mortality after acute myocardial infarction: subgroup analysis of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). Am J Cardiol. 1997;79:115-119.  
3. Al-Khadra AS, Salem DN, Rand WM, et al. Antiplatelet agents and survival: a cohort analysis from the Studies of Left Ventricular Dysfunction (SOLVD) trial. J Am Coll Cardiol. 1998;31:419-425.  
4. McAlister FA, Ghali WA, Gong Y, et al. Aspirin use and outcomes in a community-based cohort of 7352 patients discharged after first hospitalization for heart failure. Circulation. 2006;113:2572-2578.  
5. Cleland JG, Findlay I, Jafri S, et al. The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure. Am Heart J. 2004;148:157-164.  
6. Massie BM, Krol WF, Ammon SE, et al; the WATCH Study Group. Final results of the warfarin and antiplatelet trial in chronic heart failure (WATCH): A randomized comparison of warfarin, aspirin, and clopidogrel. Presented at the American College of Cardiology Annual Scientific Session 2004; March 7-10, 2004; New Orleans, Louisiana.
7. The Active Steering Committee; ACTIVE Investigators; Connolly S, Yusuf S, Budaj A, et al. Rationale and design of ACTIVE: the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events. Am Heart J. 2006;151:1187-1193.  
8. The ACTIVE Writing Group on behalf of the ACTIVE Investigators; Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomized controlled trial. Lancet 2006;367:1903-1912.
9. Jhund P, McMurray JV. Does aspirin reduce the benefit of an angiotensin-converting enzyme inhibitor? Choosing between the Scylla of observational studies and the Charybdis of subgroup analysis. Circulation. 2006;113:2566-2588.  
10. Pullicino P, Thompson JL, Barton B, et al; WARCEF Investigators. Warfarin versus aspirin in patients with reduced cardiac ejection fraction (WARCEF): rationale, objectives, and design. J Card Fail. 2006;12:39-46.  
11. The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005). Eur Heart J. 2005;26:1115-1140.  
12. Francis GS, Ganiats TG, Jessup M, Konstam MA, et al. AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2005;46:1116-1143.
13. Heart Failure Society Of America. Evaluation and management of patients with heart failure and preserved left ventricular ejection fraction. J Card Fail. 2006 Feb;12:e80-e85.

Presenter: John M. Luber, Jr, MD (Franciscan Health System, Tacoma, Washington)

New data from a study that evaluated the use of nesiritide (recombinant brain-type natriuretic peptide; BNP) in patients undergoing coronary artery bypass graft (CABG) surgery utilizing cardiopulmonary bypass indicate that mortality is reduced significantly by 180 days after surgery.^[1] The results of the Nesiritide Administered Peri-Anesthesia in patients undergoing cardiac surgery (NAPA) trial also showed trends toward decreased respiratory failure and decreased atrial fibrillation in the patients receiving nesiritide compared with those who received placebo, but there was no increase in hemodynamic parameters or in adverse effects in the nesiritide group. The pilot phase 2 trial of this investigational use of nesiritide was funded by Scios (Freemont, California), a Johnson & Johnson company, which developed and markets the drug.

Results of this study showed statistically significant benefits in postoperative renal function, a statistically significant decrease in mortality at 180 days (6.7% of patients treated with nesiritide vs 14.7% of those treated with placebo; P = .046) and a reduced length of hospital stay. The overall frequency of adverse events was similar between nesiritide and placebo.

"Patients with heart failure who require CABG surgery are critically ill and have limited treatment options," said Dr. Luber, one of the NAPA trial primary investigators. "The NAPA trial findings are encouraging because they provide important information about the safety of nesiritide and also suggest the possibility that the drug improves the outcome of these very sick patients."

Previously a number of studies had suggested that perioperative use of nesiritide might improve surgical outcomes due to improved ventricular loading conditions (decreased pulmonary arterial pressures, more effective diuresis) and/or a direct myocardial effect of nesiritide. The first results from NAPA, announced earlier this year, indicated that nesiritide had beneficial effects on postoperative renal dysfunction and outcomes.^[2]

Nesiritide is currently approved in the United States for the intravenous treatment of patients with acutely decompensated congestive heart failure (CHF) who have dyspnea at rest or with minimal activity. Warnings about renal effects have been included in the FDA-approved product labeling for nesiritide since its 2001 approval. Increases in serum creatinine are associated with the use of nesiritide at approved doses. Nesiritide can cause hypotension, and it is advised that it should be administered only in settings where blood pressure can be monitored closely. Nesiritide is also available in some countries of Central and South America, and in Israel and Switzerland, but it has not been approved by the European Medicines Agency.

NAPA I

The objective of this investigation was to evaluate the impact of perioperative administration of nesiritide on hemodynamics, adverse events, and mortality in heart failure patients undergoing cardiac surgery utilizing cardiopulmonary bypass. The prospective, multicenter, double-blind trial included 279 patients (mean age 64 years, 78% male, 83% white) from 54 centers undergoing cardiac surgery with or without mitral valve repair/replacement. All patients had NYHA class II-IV heart failure and ejection fraction ≤ 40%.

Patients were randomized to nesiritide (0.01 mcg/kg/min, no bolus) or placebo after induction of anesthesia in addition to usual care (determined by the attending physician) and continued for 24-96 hours. A total of 141 patients received nesiritide and 138 were assigned to placebo.

Postoperative Outcome

Urine output in the first 24 hours after surgery was significantly greater in patients treated with nesiritide than in those treated with placebo (2926 vs 2350 mg/mL, respectively, P < .001) (Table 1). Significantly fewer patients treated with nesiritide had a serum creatinine (SCr) increase > 0.5 mg/dL (7% vs 23%, respectively, P < .001) by hospital discharge or study day 14, whichever came first (posthoc analysis). Length of hospital stay was reduced in patients treated with nesiritide compared with placebo (9.1 days vs 11.5 days, respectively, P = .043). There were no statistically significant differences between the nesiritide and placebo groups in mean intubation time, intensive care unit (ICU) length of stay, or use of intravenous vasoactive medications.

Table 1. Postoperative Outcome Measures

Parameter	Nesiritide	Placebo	P Value
Urine output, 24 h (mL)	2926	2350	< .001
Patients with postoperativeSCr increase > 0.5 mg/dL	7%	23%	< .001
Hospital length of stay(days, mean ? SD)	9.1 ? 6.1	11.5 ? 9.8	.043

Hemodynamic Parameters

Mean pulmonary arterial pressure (MPAP) decreased by 2.8 mm Hg in the nesiritide group vs 1.9 mm Hg in the placebo group (P = .297) 24 hours after surgery. There were no differences between the nesiritide and placebo groups with regard to other hemodynamic parameters, including pulmonary capillary wedge pressure (PCWP), mean arterial pressure (MAP), central venous pressure, cardiac index, and systemic vascular resistance (SVR) (Table 2).

Table 2. Hemodynamic Parameters at 24 Hours Post Surgery

Parameter	Nesiritide Mean Change ? SD	Placebo Mean Change ? SD	P Value
MPAP (mm Hg)	-2.8 ? 7.9	-1.9 ? 7.8	.297
PCWP (mm Hg)	-3.0 ? 8.1	-1.2 ? 7.3	.239
MAP (mm Hg)	-5.5 ? 19.5	-5.3 ? 19.3	.958
Central venous pressure (mm Hg)	-1.6 ? 5.8	-1.5 ? 5.8	.840
Cardiac index (L/min/m2)	0.6 ? 0.9	0.7 ? 0.7	.429
SVR (dynes s cm-5 m2	-348.7 ? 487.7	-456.6 ? 580.2	.139

MAP = mean arterial pressure; MPAP = mean arterial pulmonary pressure; PCWP = pulmonary capillary wedge pressure; SVR = systemic vascular resistance.

Mortality

The 30-day mortality data were available for 132 patients in the nesiritide group and 127 in the placebo group, and 180-day mortality data were available for 94 and 95 patients, respectively (Table 3). Nesiritide treatment was associated with a nonsignificant trend toward decreased mortality at 30 days compared with placebo (2.8% vs 5.9%, respectively; P = .219) and a significant decrease in mortality at 180 days (6.7% vs 14.7%, respectively; P = .046) (both based on Kaplan-Meier estimates).

Table 3. Mortality at 30 Days and 180 Days

	Nesiritide n (%)	Placebo n (%)	HR	95% CI	P Value
Within 30 days	4 (2.8)	8 (5.9)	0.48	0.14-1.59	.219
Within 180 days	8 (6.7)	17 (14.7)	0.44	0.19-1.01	.046

CI = confidence interval; HR = hazard ratio.

Adverse Events

The overall frequency of adverse events was similar in nesiritide and placebo patients (Table 4). Respiratory failure and atrial fibrillation were less frequent in the nesiritide patients.

Table 4. Adverse Events

	Nesiritide (n = 141)	Placebo (n = 138)	P Value
Overall adverse events, n (%):
Any event	132 (93.6)	123 (89.1)	.205
Any serious event	43 (30.5)	51 (37.0)
Any event causing withdrawal from the study	5 (3.5)	5 (3.6)	1.00
Selected adverse events occurring in ≥ 5% of subjects, n (%):
Hypotension	36 (25.5)	43 (31.2)	.352
Atrial fibrillation	30 (21.3)	44 (31.9)	.057
Ventricular tachycardia	14 (9.9)	11 (8.0)	.676
Respiratory failure	3 (2.1)	16 (11.6)	.002
Dyspnea	9 (6.4)	7 (5.1)	.798
Acute renal failure*	10 (7.1)	17 (12.3)	.160

*Based on investigator classification without a predetermined requirement for dialysis.

Future Directions

According to Scios, the data on mortality and safety from the NAPA study are sufficiently encouraging to proceed to a phase 3 study in order to further study the use of nesiritide in patients undergoing CABG surgery with cardiopulmonary bypass. "The final data will be submitted to the FDA once the validation is complete," according to a company representative.

Details of a second NAPA trial that will start recruitment in the first half of 2007 have been released by Scios. NAPA II, a multicenter, randomized, double-blind study, aims to enroll a total of 1500 patients aged ≥ 18 years with NYHA class II-IV heart failure and ejection fraction < 40% who are scheduled for CABG surgery utilizing cardiopulmonary bypass. Patients will be randomized to treatment with an infusion of nesiritide or placebo beginning at the time frame of induction of anesthesia in addition to usual care for 24 to 96 hours. Mortality and morbidity will be assessed by evaluating multiple clinical endpoints.

Nesiritide is also being investigated for use following cardiac surgery in infants in a pilot study being carried out at Children's Hospital Boston. A total of 20 infants aged < 1 year with congenital heart disease who have undergone cardiac surgery with cardiopulmonary bypass will be recruited into the study. Patients will be eligible if they have received 2 conventional diuretics (furosemide and chlorothiazide) for ≥12 hours but have not achieved a negative fluid balance, prohibiting sternal closure or tracheal extubation. Twenty patients will be randomized to receive either of 2 study protocols: a 10-hour continuous infusion of nesiritide, a 2-hour washout period followed by a 10-hour infusion of placebo, or the study drug sequence in reverse order. The primary outcome of the study is urine output, with secondary outcomes of cardiac index and safety. The study is scheduled to be completed in January 2007.

Safety Program

As part of the clinical development program for nesiritide, Scios recently announced that a global study to further assess the benefit and safety profile of nesiritide will be carried out in patients with acute decompensated CHF, the only indication for which it is approved in the United States. The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) will be led by the Duke Clinical Research Institute in collaboration with the Cleveland Clinic Cardiovascular Coordinating Center in managing the trial.^[3] The study will evaluate nesiritide administered at the currently recommended dose of an intravenous bolus of 2 mcg/kg followed by a continuous infusion of 0.01 mcg/kg/min. Clinical endpoints may include symptom relief, quality of life, rehospitalization for heart failure, and mortality. The randomized, double-blind, placebo-controlled trial will enroll approximately 7000 patients with acutely decompensated CHF at approximately 600 medical centers in the United States, Canada, and Europe. Patient enrollment for ASCEND-HF is expected to begin in the first half of 2007.

References

1. Luber JM; The NAPA Investigators. Perioperative nesiritide use is associated with decreased 180-day mortality in heart failure patients undergoing cardiothoracic surgery. J Card Fail. 2006;12(6 Suppl):S73.  235.
2. Hebeler RF, Oz MC; the NAPA Investigators. s from the 7th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke. Poster presentations. Effect of perioperative nesiritide administration on postoperative renal function and clinical outcomes in patients undergoing cardiothoracic surgery. Circulation. 2006;113;807-808.
3. Scios selects Duke Clinical Research Institute (DCRI) to lead landmark international outcomes trial of Natrecor^? (nesiritide). September 7, 2006. Available at www.scios.com.

Presenter: John R. Teerlink, MD, University of California, San Francisco, and Veterans Affairs Medical Center, San Francisco, California

To date there has been no real success with drugs assessed for providing inotropic support in late-stage heart failure patients. A phase 1, first-in-humans clinical trial has been completed with CK-1827452, a novel, small-molecule, direct activator of cardiac myosin, administered as an intravenous formulation in healthy volunteers.^[1] The results of the trial, presented by Dr. Teerlink, a coprincipal investigator on the trial, identified the maximum tolerated dose (MTD) in these subjects as 0.5 mg/kg/h for a 6-hour infusion. At this dose, the 6-hour infusion of CK-1827452 produced a statistically significant and clinically relevant increase in ejection fraction and fractional shortening, as measured from baseline to the end of the infusion, compared with placebo. The increases in cardiac function were associated with a statistically significant prolongation of systolic ejection time.

At the MTD, CK-1827452 was well tolerated compared with placebo. Across the dosing levels evaluated in this clinical trial, infusions of CK-1827452 were characterized by linear, dose-proportional pharmacokinetics and produced dose-dependent pharmacodynamic effects. The clinical activity of CK-1827452 shown in this clinical trial was consistent with results from preclinical data that showed improved cardiac function and hemodynamics when the drug was administered in animal models of heart failure, Dr. Teerlink announced. CK-1827452 is being developed by Cytokinetics (South San Francisco, California).

Cardiac Myosin Activation

CK-1827452 is being developed as a potentially improved form of inotropic therapy based on the hypothesis that its novel mechanism may offer a safer and more effective treatment alternative for patients with compromised cardiac function. Current inotropic agents, such as beta-adrenergic receptor agonists and phosphodiesterase inhibitors, work by improving cardiac cell contractility by increasing the concentration of intracellular calcium, which indirectly activates cardiac myosin. Unfortunately, this effect on calcium levels has been linked to potentially life-threatening side effects. In addition, the inotropic mechanism of current drugs increases the velocity of cardiac contractility and shortens systolic ejection time, another undesirable result. By contrast, cardiac myosin activators have been shown to act by a novel mechanism that directly stimulates the activity of the cardiac myosin motor protein and does not alter intracellular calcium levels.

Cardiac myosin activators, such as CK-1827452, accelerate the rate-limiting step of the myosin enzymatic cycle and shift the enzymatic cycle in favor of the strongly bound force-producing state. This calcium-independent inotropic mechanism does not result in an increase in the velocity of cardiac contraction, but does lengthen systolic ejection time, which results in increased cardiac contractility and cardiac output in a potentially more oxygen-efficient manner.

Phase 1 Clinical Trial

The primary objective of the phase 1 trial, which was carried out in the United States and the United Kingdom, was to identify the MTD of CK-1827452 in healthy humans. Secondary objectives were to determine the pharmacokinetics and pharmacodynamic profile of the drug, including left ventricular (LV) systolic and diastolic function by serial echocardiography and QT-interval analysis.

A total of 34 healthy volunteers (mean age 27 years, mean ejection fraction 62%) were enrolled into 4 ascending dose cohorts. A 6-hour continuous infusion of CK-1827452 (0.005 to 1.0 mg/kg/h) or placebo was administered on each of 4 study days in each cohort, ≥ 7 days apart. Each cohort received 3 active, ascending doses of CK-1827452 and a randomized placebo infusion.

The MTD was determined to be 0.5 mg/kg/h in this trial. Doses of 0.75 and 1.0 mg/kg/h were not tolerated due to excessive prolongation of ejection time leading to decreased diastolic filling. A 0.625 mg/kg/h dose was well tolerated, but too few subjects (n = 5) received it to define it as the MTD.

At the 0.5 mg/kg/h dose, the 6-hour infusion of CK-1827452 produced a mean increase in LV ejection fraction of 6.8 absolute percentage points compared with placebo (P < .001). At the same dose, CK-1827452 also produced a mean increase in fractional shortening of 9.2 absolute percentage points vs placebo (P < .0001). These increases in indices of LV function were associated with a mean prolongation of systolic ejection time of 84 msec (P < .0001). These mean changes in ejection fraction, fractional shortening, and ejection time were dose-proportional across the range of doses evaluated in this clinical trial. In addition, CK-1827452 exhibited linear, dose-proportional pharmacokinetics across the range of doses studied.

At the MTD of ≤ 0.5 mg/kg/h for 6 hours, CK-1827452 was well tolerated when compared with placebo. At the end of the 6-hour infusion at the MTD, mean standing systolic blood pressure fell 13.0 mm Hg (P < .0001) and mean supine systolic blood pressure fell 7.4 mm Hg (P < .05) vs placebo. Systolic blood pressure decreases occurring after 6-hour infusions at doses ≥ 5.0 mg/kg/h were not accompanied by any increase in heart rate. At doses up to and through the MTD, there were no dose-related changes vs placebo in the electrocardiographic PR, QT, or QTc intervals.

Adverse Events

Up to and including the MTD, there was no dose-related increase in the overall incidence of adverse events. At doses above the MTD that were not tolerated, the CK-1827452 infusions were terminated. The 0.75 mg/kg/h and 1.0 mg/kg/h doses led to early discontinuations in 1 of 2 subjects and 2 of 2 subjects, respectively, due to symptoms of chest tightness, light-headedness, palpitations, and feeling hot. In these subjects, signs of intolerability included tachycardia (~150 bpm) and electrocardiographic changes. In one volunteer dosed at 1.0 mg/kg/h, slight, transient increases in the cardiac-specific proteins troponin I and T were observed, but the cardiac-specific fraction of the enzyme creatine kinase remained normal. Subsequent electrocardiograms and echocardiograms returned to normal in this subject, and cardiac magnetic resonance imaging enhanced by gadolinium, a test for myocardial injury, detected no cardiac abnormality. These effects are believed to be related to an excess of the intended pharmacologic effect, resulting in excessive prolongation of the systolic ejection time, and resolved promptly with discontinuation of the infusions of CK-1827452.

Conclusion

Dr. Teerlink believes that these phase 1 data are encouraging. "Patients with heart failure have had few new pharmaceutical alternatives for treating their particularly incapacitating and life-threatening disease," he said. "Based on the Phase I data, CK-1827452 looks promising as a potential addition to our treatment armamentarium for these patients in need," he predicted.

New Preclinical Data

Dr. Teerlink noted that the phase 1 results in the healthy volunteers were similar to those seen previously in normal dogs. In the animal models, underlying the increases in cardiac function (as determined by dose-dependent increases in fractional shortening) were dose-related increases in the systolic ejection time -- as were also observed in humans.

In a preclinical study evaluating the effects of CK-1827452 in both normal dogs and dogs with heart failure, presented at the HFSA meeting as a poster by You-Tang Shen, MD (Cardiovascular Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark),^[2] CK-1827452 administered intravenously at a dose of 0.5 mg/kg produced statistically significantly larger percentage increases in stroke volume and cardiac output in dogs with heart failure compared with normal dogs (11% vs 28% and 2% vs 13%, respectively, P < .05). Furthermore, when administered to dogs with heart failure as a 0.25 mg/kg bolus followed by a 72-hour infusion at 0.25 mg/kg/h, CK-1827452 increased fractional shortening (42%), stroke volume (45%), and cardiac output (32%) without increasing myocardial oxygen consumption.

Dr. Teerlink speculated that the effects of CK-1827452 might also be greater in patients with heart failure than in normal subjects.

Another poster providing supporting data on the preclinical profile of CK-1827452 was presented by Kathleen A Elias, PhD (Cytokinetics).^[3] This showed that CK-1827452, consistent with its mechanism of action, selectively activated cardiac myosin and increased contractility in cardiac myocytes in vitro without increasing intracellular calcium. CK-1827452 also significantly increased fractional shortening in vivo in normal rats, rats with heart failure, and normal dogs.

A third poster,^[4] presented by Robert L Anderson (Cytokinetics), provided additional data validating the mechanism of another cardiac myosin activator, CK-1316719, which increased contractility in myocytes from sham and heart failure rats equivalently without increasing intracellular calcium.

Developmental Status

CK-1827452 is also in development for the treatment of chronic heart failure via oral administration. A phase 1 clinical trial to evaluate the pharmacokinetic profile of CK-1827452 when administered orally was initiated in August 2006 and CK-1827452 is expected to enter an international phase 2 clinical trials program in patients with heart failure during the second half of 2006. This program is planned to evaluate CK-1827452 in a range of patients including those with stable heart failure, inducible ischemia, impaired renal function, and acute heart failure. The goal is to test the safety and efficacy of CK-1827452, in both intravenous and oral formulations, as a potential treatment of heart failure across the continuum of care in both the hospital and outpatient settings.

References

1. Teerlink JR. The selective cardiac myosin activator CK-1827452, a calcium-independent inotrope, increases LV systolic function by increasing ejection time: results of a first-in-human study of a unique and novel mechanism. Presented at the 10th Annual Scientific Meeting of the Heart Failure Society of America; September 10-13, 2006; Seattle, Washington.
2. Shen Y-T, Vatner SF, Morgans DJ, et al. Activating cardiac myosin, a novel inotropic mechanism to improve cardiac function in conscious dogs with congestive heart failure. J Cardiac Fail. 2006;12(6 Suppl):S87.  281.
3. Anderson RL, Sueoka SH, Lee KH, et al. In vitro and in vivo characterization of CK-1827452, a selective cardiac myosin activator. J Cardiac Fail. 2006;12(6 Suppl):S86.  277.
4. Anderson RL, Kawas RF, Poklrovskii MV, et al. Cardiac myosin activator CK-1316719 increases myofibril ATPase activity and myocyte contractility in a rat model of heart failure. J Cardiac Fail. 2006;12(6 Suppl):S88.  283.

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