November 15, 2005 • www.familypracticenews.com Cardiovascular Medicine 13 Drug Combo Reverses Left Ventricular Remodeling

BY DAMIAN McNAMARA curves spread out remarkably after that,” Jay with the combination and 341 with place- “striking difference between groups” that Miami Bureau N. Cohn, M.D., said during a late-breaking bo. supports the cardiac remodeling im- clinical trial session at the annual meeting At 6 months there was a significant in- provements in the study. B OCA R ATON, FLA. — Fixed-dose of the Heart Failure Society of America. crease in ejection fraction in the combi- Another meeting attendee asked how isosorbide dinitrate and hydralazine sig- Dr. Cohn and his associates performed a nation group versus placebo, said Dr. well the BNP values tracked with changes nificantly reduces left ventricular volume subanalysis of the A-HeFT data to deter- Cohn, professor of medicine and director to left ventricular volume. “We don’t and increases ejection fraction in African mine whether improvements in left ven- of the Rasmussen Center for Cardiovas- know that yet, the tracking between the American patients with moderate to se- tricular structure and function could explain cular Disease Prevention at the Universi- two is not always perfect,” Dr. Cohn said. vere heart failure, according to a sub- the improvement in survival. They com- ty of Minnesota, Minneapolis. There was “BNP is not always perfect. BNP is a con- analysis of the African American Heart pared echocardiographic findings and blood also a highly significant difference in tinuum, but the lower the better.” Failure Trial. brain natriuretic LVIDd in the treat- Another audience member asked Dr. Decreases in brain natriuretic peptide peptide (BNP) sam- ment group versus Cohn if remodeling was dose dependent. corresponded with the 6-month improve- ples taken at base- ‘I would be the placebo group, “We haven’t looked at that yet,” he replied. ments in cardiac remodeling. line and after 6 surprised if the ... he added. “This is really the first look at these data.” In the African American Heart Failure months of treat- remodeling is A meeting at- He and his associates plan to perform sub- Trial (A-HeFT), the drug combination ment. One cardiolo- confined to the tendee asked about group analyses in the future. (BiDil, Nitromed Inc.) was associated with gist evaluated all the African American possible variation “I would be surprised if the benefit on an increase in survival of 43% for African digitized echocar- population.’ with the measure- remodeling is confined to the African Americans with moderate to severe heart diograms in blinded ments used in the American population,” Dr. Cohn said. failure (N. Engl. J. Med. 2004;351:2049-57). fashion. DR. COHN study. “I’m more “We need to do that study.” The magnitude of this finding surprised Of the 1,050 self- comfortable with “The combination of isosorbide dini- some because the A-HeFT patients were identified African Americans enrolled in A- the consistency of the LVIDd measure- trate and hydralazine induces regression of already aggressively treated for heart fail- HeFT, 666 had ejection fraction values ments, compared with the ejection frac- left ventricular remodeling in patients al- ure: 87% were already taking β-blockers, recorded at baseline and 6 months. Of this tion measurements, which can be inter- ready treated with neurohormonal in- 78% were on ACE inhibitors, 39% were on group, 329 were treated with combination preted differently,” Dr. Cohn said. hibitors,” Dr. Cohn concluded. “These aldosterone inhibitors, and 28% were tak- therapy and 337 with placebo. In addition, The mean baseline BNP level was 300 data provide further support for the grow- ing angiotensin receptor blockers. there were 678 participants with left ven- pg/mL. By 6 months, the treatment group ing database that favorable effects on out- Regarding A-HeFT mortality, “the sur- tricular internal diameter in diastole experienced a greater mean decrease (28 comes in heart failure can be attributed to vival benefit versus placebo became obvious (LVIDd) values taken at baseline and 6 pg/mL), compared with the placebo favorable effects on left ventricular struc- at 6 months or 7 months, and then the months. Of this group, 337 were treated group (11 pg/mL). Dr. Cohn called this a tural remodeling. ■ Cochrane Review Finds Use β-Blocker Reverses Remodeling in For Digoxin in Heart Failure Asymptomatic Heart Failure Patients B OCA R ATON, FLA. — A β-block- the heart known as remodeling, which BY BRUCE JANCIN of digoxin on mortality—namely, that there er can reverse cardiac remodeling and is initially compensatory but ultimate- Denver Bureau is none. increase left ventricular ejection frac- ly maladaptive,” said Dr. Colucci, sec- In the DIG trial, however, there was a tion in asymptomatic heart failure pa- tion chief of cardiovascular medicine at VANCOUVER, B . C . — The latest nonsignificant trend for fewer deaths from tients, according to a double-blind, ran- Boston University. Cochrane systematic review of digoxin for heart failure in digoxin-treated patients and domized, placebo-controlled study Left ventricular end systolic volume in- treatment of heart failure patients in sinus a hint that the inotrope may have caused presented at the annual meeting of the dex was measured echocardiographical- rhythm paints a picture of a more than 200- more arrhythmia deaths, although this Heart Failure Society of America. ly after 1 year. This index decreased by year-old drug that’s still clinically useful, al- wasn’t a prespecified study end point. Metoprolol succinate extended-re- 15 mL/m2 with the 200-mg dose of though it has no effect on mortality, William Digoxin’s effect on deterioration in clini- lease tablets (Toprol-XL, AstraZeneca) metoprolol, by 8 mL/m2 with the 50-mg B. Hood Jr., M.D., said at a meeting sponsored cal status was much more clear cut in the are indicated for treatment of New dose, and by 4 mL/m2 with placebo. by the International Academy of Cardiology. metaanalysis. The odds ratio for that end York Heart Association class II and III During the same year, LVEF increased “It’s probably not point was 0.31, patients with heart failure of ischemic, 6% with the 200-mg dose, 4% with the first-line therapy. It’s meaning patients hypertensive, or cardiomyopathic ori- 50-mg dose, and 0% with placebo. not very powerful. Digoxin for heart randomized to digox- gin. In symptomatic patients with heart “The REVERT study results show a But it’s available for failure is in were 69% less like- failure and left ventricular systolic dys- reduction in this measure of left ven- patients who are not ‘probably not ly to show significant function, Toprol-XL reduced left ven- tricular volume in asymptomatic heart fully responsive to first-line therapy. clinical deterioration tricular volumes after 6 months of failure patients with left ventricular sys- other agents that It’s not very than were control pa- treatment in previous research, said tolic dysfunction,” and they provide have become first- powerful.’ tients. The third end Wilson S. Colucci, M.D. scientific data on cardiac remodeling in line treatments—the point used in the To determine whether the once-dai- such patients, Dr. Colucci said. ACE inhibitors, β- DR. HOOD metaanalysis was ly agent provides a similar benefit in The participants received metoprolol blockers, spironolac- hospitalization for asymptomatic patients, Dr. Colucci and or placebo in addition to their existing tone, and the angiotensin receptor block- worsening heart failure. Patients on digox- his colleagues randomized 164 NYHA medications. For example, at study en- ers,” added Dr. Hood, lead author of the in were 32% less likely to experience it. class I patients at 44 U.S. sites to receive try, 92% were taking an ACE inhibitor recent Cochrane review and a cardiologist Two studies included in the metaanalysis a 50-mg or 200-mg dose of metoprolol or angiotension receptor blocker, and at the University of Washington, Seattle. were designed to learn whether concomi- extended-release tablet daily or placebo. 65% were taking a diuretic. There were The metaanalysis was restricted to ran- tant ACE inhibitor therapy mattered in pa- All the participants in the Reversal of “very minimal changes” in medications domized, double-blind, placebo-controlled tients randomized to digoxin or placebo. Ventricular Remodeling with Toprol- during the study, and no participant trials involving adults followed for at least 7 Both showed that patients on an ACE in- XL (REVERT) study had a baseline left used a cardiac resynchronization ther- weeks. Thirteen trials totaling nearly 7,900 pa- hibitor plus digoxin did better than those on ventricular ejection fraction (LVEF) be- apy device, he said. tients qualified, including the largest of all an ACE inhibitor plus placebo. low 40%. All also had evidence of car- “There was a very strong relationship digoxin studies: the 6,800-patient, 3-year Dig- However, the effects of digoxin in patients diac remodeling at baseline, defined as between dose and heart rate decrease,” italis Investigation Group (DIG) trial (N. Engl. on other agents that have become first-line a left ventricular end diastolic volume he said. “We have not looked at J. Med. 1997;336:525-33). therapies in heart failure more recently index greater than 75 mL/m2. Mean whether anything in the demographics Why even bother doing a metaanalysis than the ACE inhibitors, including β-block- age was 66 years, 25% were women, predicted that change.” when one trial is so dominant in size? Dr. ers and aldosterone antagonists, haven’t and 54% had heart failure of an is- Dr. Colucci has no conflict of interest Hood explained that the smaller trials are been systematically studied. For ethical rea- chemic etiology. disclosure regarding Toprol-XL. Its mak- helpful in that each consistently reached the sons it’s highly unlikely such trials will ever “In heart failure there are progressive er, AstraZeneca, sponsored the trial. same conclusion as DIG regarding the effect be done, Dr. Hood said. ■ enlargement and structural changes to —Damian McNamara