Barcelona, Spain - The one-year risk of sudden death in patients with stable chronic heart failure can be cut significantly if they initiate drug therapy with a beta blocker, to which an ACE inhibitor is later added, instead of starting on each drug in the reverse order, suggests a post hoc analysis of the third Cardiac Insufficiency Bisoprolol Study (CIBIS 3) [1].

The randomized, open-label trial conducted in 20 countries had previously demonstrated that the order in which a beta blocker and an ACE inhibitor are initiated in patients with mild to moderate chronic HF has no significant effect on mortality or hospitalization risk [2]. Standard practice, however, was to lead off with an ACE inhibitor as monotherapy and then later add a beta blocker.

The latest finding from CIBIS 3, reported here today at the World Congress of Cardiology 2006, suggests there may be an important advantage to the reverse sequence for introducing the drugs. Patients in the trial for whom the initial drug was bisoprolol, to which enalapril was added later, showed a 46% drop in the risk of sudden death over the first year compared with those who received the ACE inhibitor as the initial monotherapy.

In his presentation of the post hoc analysis, CIBIS 3 investigator Dr Ronnie Willenheimer (Lund University, Malmö, Sweden) observed further that "the early reduction in sudden death with bisoprolol [monotherapy] was accompanied by a nonsignificant reduction in all-cause death of a similar magnitude, indicating that this strategy does not simply alter the mode of death to progressive heart failure or other nonsudden death."

As reported at the September 2005 sessions of the European Society of Cardiology and covered then by heartwire, CIBIS 3 had randomized 1010 patients aged 65 or older with stable NYHA class 2-3 heart failure and an LVEF <35% to therapy with either bisoprolol with the later addition of enalapril or the reverse drug sequence. Patients were started on bisoprolol at 1.25 mg/day, with stepwise titration to 10.0 mg/day over 10 weeks, and enalapril at 2.5 mg twice daily titrated to 10 mg/day bid over four weeks. The initial monotherapy, regardless of which drug led off the regimen, was maintained for six months. The bisoprolol-first approach emerged as statistically "noninferior" to the enalapril-first strategy for the primary end point of all-cause mortality or hospitalization over a mean follow-up of 1.2 years. In Willenheimer's presentation of the trial's sudden-death findings, the follow-up averaged about 5.5 months.

CIBIS 3: Sudden-death and all-cause mortality risk reduction with bisoprolol monotherapy compared with enalapril monotherapy

End point	HR (95% CI)	p
Sudden death
Monotherapy phase	0.50 (0.21-1.16)	0.107
1 year	0.54 (0.29-1.00)	0.049
End of study	0.84 (0.51-1.38)	0.487
All-cause mortality
Monotherapy phase	0.72 (0.42-1.24)	0.24
1 year	0.69 (0.46-1.02)	0.06
End of study	0.88 (0.63-1.22)	0.44

"My recommendation is to give all patients with stable new-onset heart failure bisoprolol as early as possible," Willenheimer told heartwire. "Personally, I would rarely not start with bisoprolol, because there are no advantages to starting with an ACE inhibitor." He said the primary focus of therapy in patients with recently diagnosed heart failure should be to prevent sudden death, "the most common mode of death in the early stage. . . . If you can do that, you can [later] combine different therapies to improve symptom status and quality of life."

"I feel that beta-blocker therapy can be initiated first in selected heart-failure patients, but the CIBIS 3 trial [sudden-death] results do not allow us to recommend this strategy in clinical practice," discussant Dr Luigi Tavazzi (Fondazione IRCCS Policlinico San Matteo, Pavia, Italy) said after Willenheimer's presentation. The sudden-death data, he said, have limitations that leave them vulnerable to "overinterpretation."

For example, Tavazzi observed, the lower one-year sudden-death rate in the bisoprolol monotherapy group reached a p value of only 0.049, "a very borderline value, around the minimal level of significance that the scientific community accepts." Moreover, sudden death was not in the trial's protocol as a primary or secondary end point, nor was an outcomes analysis at one year prespecified, he said. Therefore, the sudden-death rate difference could have been "statistically significant by chance."

Tavazzi also seemed to question the practical relevance of the trial's dosing protocols: "I feel that any clinical strategy based on nine up-titration steps over eight months will never be incorporated as such into clinical practice."

Willenheimer told heartwire that he was "surprised" by Tavazzi's apparent suggestion that the CIBIS 3 titration schedule may be too arduous for many clinicians or patients. In many countries, he said, bisoprolol is commonly titrated to a maintenance dose according to the schedule used in CIBIS 3, "which is evidence-based."

CIBIS 3 was sponsored by Merck KgaA (Darmstadt, Germany). Willenheimer reports having received honoraria from Merck.

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