The Impact of Beta‐Receptor Blocker Addition to High‐Dose Angiotensin
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Clin. Cardiol. 2 I, 899-904 ( 1998) The Impact of Beta-Receptor Blocker Addition to High-Dose Angiotensin- Converting Enzyme Inhibitor-Nitrate Therapy in Heart Failure T. BARRYLEVINE, M.D.. ARLENEB. LEVINE, M.D., STEVEN J. KETEYIAN. PH.D.," BARBARANAR~NS.R.N. Michigan Institute for Heart Failure and Transplant Care, Botsford General Hospital, Fmington Hills; *Henry Ford Hospital, Detroit. Michigan, USA Summary Results: New York Heart Association classification im- proved from 2.9 k 0.7 to 1.8 k 0.8 on lisinopril-nitrates (p< BtrcAgtnutid: The natural history of heart failure is one of 0.05),and to 1 .5 k 0.5 with the addition of beta blockade (p = continued worsening of cardiac function. Beta-receptor block- NS). On follow-up, peak oxygen consumption rose from 17 er therapy has been eff'ective in improving clinical status and k 7 ml 02kg/min at baseline to 21 k 5 ml Ozn<g/min at 6 left ventricular function in patients with heart failure. Sirnilar- months on lisinopril-nitrates (p = 0.06) without further change ly, high doses of angiotensin-converting enzyme (ACE) in- on beta blockade. Ejection fraction rose from 19 k 8 to 33 k hibitors with nitrates partially reverse the ventricular reniodel- 14% on lisinopril-nitrates at 6 months (p= 0.005) and to 36 k ing of heart failure. 18% on beta blockade at 12 months (p= NS). Hypothesis: We tested the hypothesis that beta-blocker Conclusion: High-dose ACE inhibitor-nitrate therapy sig- therapy added to high-dose ACE inhibitor-nitrates would nificantly improved patient clinical status and left ventricular potentiate the reversal of heart failure. systolic function in heart failure. The addition of beta-receptor Methods: Thirteen patients, aged 52 k 8 years, with moder- blockade over and above high-dose ACE inhibitor-nitrates ate to severe heart failure, 12 of whom were referred for trans- was well tolerated but had no further impact on symptomatic plant consideration, with heart failure duration of 4.8 k 2.2 status, exercise tolerance, or left ventricular systolic function. years. were prospectively followed for 12 months. Baseline The potential for phmacologic reversal of heart failure re- echocardiographic ejection fraction was 19 k 8%. and pre- modeling may be finite despite the use of complementary senting New York Heart Association class was 2.9 k 0.7. therapies. Larger placebo-controlled and randomized trials of Angiotensin-converting enzyme inhibitors and nitrates were beta-receptor blockade added to high-dose ACE inhibitor- uptitrated over 6 months to a final dose of lisinopril 53 -+ 31 nitrate therapy are needed to confirm these observations. mdday, and isosorbide dinitrate 217 k 213 mg/day. At 6 months, beta-blocker therapy with atenolol was initiated and titrated to a final dose of 46 r 23 mg/day. Two-dimensional Key words: angiotensin-converting enzyme inhibitors, ni- Doppler echocardiography and metabolic stress testing were trates, beta-receptor blockade, heart failure therapy, left ven- performed at baseline, at 6 months on lisinopril-nitrates only, tricular reverse remodeling and at 12 months on combined ACE inhibitor-nitrate and beta-blocker therapy. Introduction Despite numerous advances in therapy for cardiovascular disease, heart failure continues to be a major and growing pub- lic health concern. The prognosis for severe heart failure in the absence of medical intervention is grave, marked by progres- Addrew for reprints: sive symptomatic deterioration and death. I. T. Barry Levine, M.D. Over the last decade, major trials have defined treatment Michigan Inslitute for Heart Failure and Transplant Care strategies that improve the prognosis for patients with heart Botxlord General Hospital failure. Therapy with angiotensin-converting enzyme (ACE) 28050 Grand River Ave. inhibitors has improved both patient symptomatic status and Farniingm Hills. MI 48336. USA survival in mild to severe heart failure?' This clinical im- Received: June 8. 1998 provement has been associated with a partial arrest of the oth- Accepted with revision: August 24, 1998 erwise inevitable continued deterioration in left ventricular OO( 1 Chi. Cardiol. Vol. 2 I. December 1998 systolic function. resulting in stabilization of left ventricular 80 mg/day. Isosorbide dinitrate was initiated, and doses were end-diastolic size and ejection increased to a maximal dose of480 mg/day for any ofthe fo- The addition of beta-receptor blockade to heart failure lowing conditions: continued symptomatic ischemia. eleva- therapy has allowed further improvement in symptomatic tion of right ventricular filling pressures per physical exami- status over and above conventional dose ACE inhibitor ther- nation, pulmonary hypertension in excess of40 nimHg. mod- ;ipy, resulting in a reduction in transplant requirement andor erate to severe left ventricular chamber enlargement (16 cm in improved Of importance is the fact that beta- left ventricular end-diastolic diameter), and/or moderate to reccptor blockade h;is actually led to a partial reversal of severe mitral regurgitation as estimated on Doppler echocx- heart l‘uilure-associated deterioration in systolic function. diographic examination. Dose titration was limited in patients xhieving signiticant increases in left ventricular ejection experiencing lightheadedness or other signs of intolerance, fraction.”. IJ but was resumed after days to weeks of re-equilibration. For We have recently reported that high doses of ACE inhibitors hypotensive patients with systolic arterial blood pressure < 90 i ti conjunclion with nitrates may also reverse heart failure re- mmHg, diuretic dosages were carefully lowered to allow in- modeling, increasing left ventricular ejection fraction while creases in vasodilator therapy. All patients were maintninccl cIecre;ising left ventricdar size.I5.Ih on digitalis. Thi.; study was designed to determine prospectively whe- Beta-I receptor blockade was initiated at 6 months follow- ther the acldition of beta-receptor blocker therapy to high-dose ing maximal intensification of lisinopril-nitr~itetherapy with ACE inhibitor-nitrate therapy has an additive impact on pa- atenolol at 6.25 mg/day, with upward dose titrations at 6.25 mg tient clinical status and left ventricular remodeling. We hypo- increments to a maximal dose of50 mg twice daily. Dose in- thesized that beta blockade added to high-dose ACE inhbitor- creases were limited by reaching the target dose, by drug intol- nitrates would further potentiate the reversal of heart failure. erance or side effects, by achieving relief of sytnptoiiis. or by reaching aresting heart rate of SS4S beats/min. Methods Patient Follow-Up Sludy Patients Two-dimensional echocardiogratns were obtained at base- line and semiannually. Echocardiographic measurenients All patients referred and followed with severe heart failure were made in a blinded fashion by staft‘echocardiographers were prospectively entered into a heart failure database. Pa- not involved in the heart failure program. Mitral regurgilation tients with unstable ischemic syndromes, severe obstructive was graded as follows: 1 + = mild, 2+ = mild/moderate, 3+ = valvular pathology. primary hypertrophic, restrictive, and in- moderate, and 4+ = severe. liltrative cnrdiomyopathies, pericardial constriction, severe In 8 of 13 patients, exercise aerobic capacity was cletcr- hepatic, renal. and pulmonary end-organ disease were not en- mined semiannually in coiijunction with echocardiography. tcrecl. Patients in our program had echocardiographic follow- The metabolic stress test employed a stationary bicycle proto- up routinely pcrfot-med every 6 months. col with load increments of25 W every 3 min up to symptom- We prospectively Ihllowed I3 sequential patients clinically limiting maximal fatigue. A metabolic cart (Sensormeclics. and with echocardiographic studies at baseline, at 6 months Yorba Linda, Calif.) was used to assess expired gases for oxy- while on inaxiiniil ACE inhibitor-nitrate therapy without beta gen consumption (V02) every IS s. blockacle. and at I2 months following the addition of beta- receptor blocker therapy. Eight of these patients also had serial Statistical Analysis xciniannunl measurements of aerobic capacity. Each patient All 13 patients in this study spent at least I2 months in fol- strvecl ;IS hisher own control. low-up. Data are presented as mean standard deviation. To tietermine the impact of beta-receptor blockade with f Dilferences between group mean values were assessed with high-close ACE inhibition in a larger patient cohort, we also analysis of variance (Statview 4. I, Abacus Concepts, Inc.. retrospectively reviewed baseline and 12-month follow-up Berkeley, Calif.), and a Student-Newman-Keuls test. For di- ecliocurdiographic data on all database patients on > 40 mg/ chotomous data, the chi-square test was iised. Statistical sig- clay oi’ lisinopril (11 = 8S), of whom 36 were receiving beta- nificance was defined as p < 0.05. rcccp~orblocker therapy. Mediral ‘I’herapy Results For the I3 patients, ACE inhibitor-nitrate therapy was in- Patient Characteristics tensitid, as previously outlined, guided by hernodynamic re- sponsc and tindings on physical examination.Ih Lisinopril Table I presents demographic and clinical characteristics at was increasingly uptitrated in the presence of continued ade- baseline for the 13 patients. Nine patients were Caucasian, and quate systemic systolic arterial blood pressure (> 90 mmHg) 10 were men. Twelve of the 13 patients had been referred for and preserved end-organ perfusion up to a maximal