ACTIV in CHF: Acute and Chronic Therapeutic Impact of a Vasopressin 2 Antagonist (Tolvaptan) in Congestive Heart Failure

Luis Gruberg, MD, FACC

Disclosures

December 30, 2003

Editorial Collaboration

Medscape &

Presenter: Mihai Gheorghiade, Northwestern University Feinberg School of Medicine (Chicago, Illinois)

Heart failure is a major health concern and is the only manifestation of cardiovascular disease that is actually becoming more prevalent. It is responsible for more than 1 million hospitalizations per year in the United States and leads to high mortality and rehospitalization rates.

The progressive form of the disease is "congestive heart failure" (CHF), reflecting the fluid retention and overload that occurs with poor renal function and hyponatremia. An easy and reliable measure of CHF status is patient weight, which varies with the amount of fluid retention and should be monitored daily. Diuretics have traditionally been the mainstay of treatment, but they are associated with electrolyte abnormalities and impaired kidney function. It has also been suggested that non-potassium-sparing diuretics may actually increase mortality in patients with CHF.

Previous studies have shown that levels of the endogenous hormone vasopressin are elevated in CHF patients and may be the contributing factor of fluid retention and hyponatremia. Tolvaptan (Otsuka Pharmaceutical Co, Ltd.; Rockville, Maryland) is a new oral vasopressin receptor antagonist that can lessen reliance on diuretics by reducing body weight and normalizing serum sodium levels in CHF patients without impairing renal function or electrolyte balance.

Aim

The phase 2 Acute and Chronic Therapeutic Impact of a Vasopressin 2 Antagonist (Tolvaptan) in Congestive Heart Failure (ACTIV in CHF) study was conducted to assess the acute and chronic effects of varying doses of tolvaptan in patients with worsening CHF requiring hospitalization.

Endpoints

The study's primary endpoints included:

  • Acute: Body weight reduction at 24 hours after randomization

  • Chronic: Reduction of worsening of CHF (death, rehospitalization, or unscheduled visits for CHF) at 60 days after randomization

Key secondary objectives included:

  • Body weight at discharge

  • Urine output

  • Serum electrolytes

  • Use of loop diuretics

  • Clinical congestion

Study Design

ACTIV in CHF was a prospective, international, multicenter, double-blind, placebo-controlled trial that enrolled patients with exacerbation of known CHF (ejection fraction < 40%) and fluid overload requiring hospitalization. Patients were randomized within 72 hours of admission to 1 of 4 regimens: (1) once-daily tolvaptan 30 mg plus standard treatment (n = 78), (2) once-daily tolvaptan 60 mg plus standard treatment (n = 84), (3) once-daily tolvaptan 90 mg plus standard treatment (n = 77), or (4) placebo plus standard treatment (n = 80). Patients were followed for 60 days.

Patients with a recent myocardial infarction, recent cardiac surgery, systolic blood pressure < 110 mm Hg, life-threatening arrhythmias, or severe renal impairment were excluded from the study.

Results

A total of 319 patients were enrolled at 34 US and 11 Argentinian centers. All 4 treatment groups were similar with regard to baseline clinical characteristics and baseline concomitant therapy (Tables 1 and 2).

Table 1. ACTIV in CHF: Baseline Clinical Characteristics
Characteristic Placebo
(n = 80)
Tolvaptan
30 mg (n = 78)
Tolvaptan
60 mg (n = 84)
Tolvaptan
90 mg (n = 77)
Age (yrs) 62 60 62 62
Female (%) 25 32 40 21
Diabetes (%) 46 50 45 46
Hypertension (%) 75 76 69 68
S/P MI (%) 43 35 35 36
Atrial fibrillation (%) 33 37 42 34
S/P CABG (%) 35 24 26 39
Ejection fraction (%) 24 25 24 24
SBP (mm Hg) 116 +/ 20 123 ± 23 119 ± 17 119 ± 22
Edema (%) 59 68 71 75
CABG, coronary artery bypass graft surgery; MI, myocardial infarction; SBP, systolic blood pressure; S/P, status post
Table 2. ACTIV in CHF: Baseline Concomitant Therapy
Medication Use (%) Placebo
(n = 80)
Tolvaptan
30 mg (n = 78)
Tolvaptan
60 mg (n = 84)
Tolvaptan
90 mg (n = 77)
ACE inhibitors/ARBs 85 83 82 78
Diuretics 96 99 96 99
Digoxin 71 68 64 69
Beta-blockers 40 47 45 29
Nitrates 43 27 26 29
Spironolactone 40 39 36 38
ACE, angiotensin-converting enzyme; ARBs, angiotension receptor blockers

A significant proportion of patients did not reach the time goal and discontinued treatment before the 60-day follow-up (30% to 52%) (Table 3).

Table 3. ACTIV in CHF: Clinical Course
Placebo
(n = 80)
Tolvaptan
30 mg (n = 78)
Tolvaptan
60 mg (n = 84)
Tolvaptan
90 mg (n = 77)
Treated patients (n) 79 78 84 76
Discontinued (%) 30 38 52 42
Mean exposure (days) 43 45 36 39

At 24 hours and during hospitalization, all 3 doses of tolvaptan were associated with significant reductions in body weight when compared with placebo (Figure 1). These weight reductions were associated with a significant increase in urine output and an improvement in clinical signs and symptoms of CHF. An increase in sodium to normal levels was also observed in patients treated with tolvaptan.

Figure 1. ACTIV in CHF: body weight changes at 24 hours.

There was no difference in the rate of total in-hospital mortality or worsening of heart failure rates among the tolvaptan and placebo groups (Table 4).

Table 4. ACTIV in CHF: Clinical Events
Placebo
(n = 80)
Tolvaptan
30 mg (n = 78)
Tolvaptan
60 mg (n = 84)
Tolvaptan
90 mg (n = 77)
In-hospital mortality (%) 2.5 0 1.1 0
Worsening heart failure (%) 30 29 43 27

An unadjusted analysis comparing all doses of tolvaptan with placebo found that at 60 days, all-cause mortality was significantly increased in patients with hyponatremia, renal insufficiency, and congestion on admission who were randomized to placebo, and it seems that these groups of patients derived the greatest benefit from active treatment (Figure 2). Regarding adverse events, hypotension was not a problem in the active treatment groups and the most common complaint was thirst. The most commonly reported adverse event was thirst; hypotension was not reported in the active treatment groups.

Figure 2. ACTIV in CHF: 60-day all-cause mortality.
Conclusions

On the basis of the findings of the ACTIV in CHF study, investigators concluded that:

  1. This was the first trial to assess the acute and chronic effects of an oral investigational agent in patients hospitalized with heart failure.

  2. Tolvaptan in addition to standard therapy produced rapid and sustained decreases in body weight during hospitalization.

  3. There was no apparent dose response with the doses tested in the study.

  4. The addition of tolvaptan was not associated with acute or chronic changes in blood pressure, changes in serum potassium, or increases in BUN and creatinine.

  5. Tolvaptan was associated with normalization of serum sodium in patients with hyponatremia.

  6. Compared with placebo, use of tolvaptan was not associated with any significant difference in worsening heart failure at 60 days (eg, with regard to rates of death, rehospitalization, and unscheduled visits for CHF).

  7. There was a trend toward lower mortality with tolvaptan in patients with clinical congestion, hyponatremia, or abnormal renal function.

  8. The effects of tolvaptan on mortality in patients hospitalized for CHF are currently being tested in the international Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan (EVEREST).

Discussant

Mariell Jessup, MD, Heart Failure/Transplant Program (Philadelphia, Pennsylvania), told attendees that vasopressin has extremely important physiologic functions and plays a critical role in the treatment of patients with CHF. Due to this important role, vasopressin has been the subject of intense research and discussion for the past 20 years. According to the ACTIV in CHF study, the greatest benefit is seen in the sickest patients.

There are important questions that this study will help us understand, such as: What are the effects of vasopressin when used concomitantly with aldosterone antagonists and ACE inhibitors? Dr. Jessup acknowledged that it would be very difficult for any new drug to show a significant improvement in mortality rates. Nevertheless, she is optimistic of the results.

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