Clin. Cardiol. 2 I, 899-904 ( 1998)

The Impact of Beta-Receptor Blocker Addition to High-Dose - Converting Enzyme Inhibitor-Nitrate Therapy in Failure

T. BARRYLEVINE, M.D.. ARLENEB. LEVINE, M.D., STEVEN J. KETEYIAN. PH.D.," BARBARANAR~NS.R.N. Michigan Institute for 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

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 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 . 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 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 (> 90 mmHg) 10 were men. Twelve of the 13 patients had been referred for and preserved end-organ up to a maximal dose of transplant consideration. T.B. Levine et al.: Beta blocker addition to high dose ACE inhibitor-nitrates 90 1

TAHLI:I Baseline characteristics of 13 patients with cardiomyo- from an initial value of 17 k 7 to 21 & 5 ml O2/kg/min (p = pathy 0.06).No further change was observed while patients were on beta blockade (Table 11). Age (yearsj S2+8 Sex (male/female) 10/3 Race (white/nonwhite) 9/4 Echocardiographic Fmdings New York Heart Association class 2.9 k 0.7 Heart failure duration (years) 4.8 k 2.2 Ten of the 13 patients had an increase in left ventricular Ischemiclnonischemiccardiomyopathy 2/11 ejection fraction while on ACE inhibitor-nitrates alone, and 4 Heavy alcohol use 0 of 13 patients had a subsequent drop in ejection fraction while Peripartuni 0 on beta blockade. For all patients, average ejection fraction Heart rate (min) 92k 18 changed from 19 k 8 to 33 & 14% at 6 months on ACE inhib- Systemic systolic blood pressure (mniHg) 122k27 itor-nitrates (p = 0.005),and to 36 k 18% at I2 months on beta Ejection fraction (76) 19*8 blockade (p = NS) (Fig. 1). This change was associated with Values are presented as mean ?standard deviation. an overall reduction in the severity of mitral regurgitation from 1.9 rt 1.4 to 0.6 0.9 at I2 months (p = 0.02). To determine whether the presence of beta-receptor block- ade had any differential impact on left ventricular function Medications with high-dose ACE inhibition, >40 mg/day of lisinopril, in a larger group of patients, we retrospectively reviewed the All patients were maintained on digoxin. Diuretics were echocardiographic findings at baseline and at 12 months for discontinued in four patients. Lisinopril was uptitrated from 85 patients on lisinopril70 k 16 mg/day, with 36 of the 85 pa- 15 rt I3 to 53 rt 3 1 mg/day, isosorbide dinitrate from 19 * 36 tients on atenolol54 & 33 mg/day. For the group as a whole, to 2 17 k 2 I3 mg/day. All patients tolerated the addition of left ventricular ejection fraction increased (19 k 7 to 3 I rt 6%, beta blockade, with a final atenolol dose of46 k 23 mglday. p = 0.0005)with a decline in the severity of mitral regurgita- tion (2.1 k 1.3 to 1.2 k 1.3, p = 0.01). However, both actual Patient Clinical Status 12-month echocardiographic findings as well as calculated changes were not significantly different for patients in the presence or absence of beta-receptor blockade (Table 111). In follow-up, no patient required intravenous inotropic support or heart transplant, and no patient died. As a group, New York Heart Association classification improved from 2.9 * 0.7 at baseline to 1.8 2 0.8 on lisinopril-nitrates (p < Discussion 0.05),to a final 1.5 k 0.5 (p = NS) on beta blockade. Systolic arterial blood pressure remained unchanged over time. There We found that uptitration to high-dose ACE inhibitor-ni- was an overall significant decline in heart rate from baseline trate therapy effectively reversed the clinical severity of heart to 12 months (p = 0.005),decreasing from 91 k 18 to 8 1 & 17 failure, improving symptomatic and functional status as well on ACE inhibitor-nitrates alone, and to 71 f 9 with beta as left ventricular systolic function. The subsequent addition blockade (p = NS). Heart failure-related hospitalizations per of beta blockade was well tolerated. Although symptoms and year overall decreased (p = 0.002), from 1.1 k 0.9 to 0.5 k 0.9 left ventricular systolic function tended to improve on beta with vasodilator therapy only, and no patient required hospi- blockade, these trends were statistically not significant and talizations while on beta blockers (p = NS). For the eight pa- thus did not substantiate our hypothesis that the addition of tients who underwent assessment of exercise capacity, peak beta blockers would significantly potentiate the clinical bene- oxygen consumption tended to increase while on vasodilators fit of high-dose ACE inhibitor-nitrate therapy.

TABLEI1 Initial, 6 month, and 12 month clinical parameters 6 Months ACE I2 Months p Value inhibitor- beta blocker initial-12 Clinical parameter Initial nitrates alone added months

Heart rate (n = 13) 91 k 18 81 + 17 71 +9 0.005 Systemic systolic blood pressure (rnmHg) (n = 13) 122k27 116+ 18 121 rt 14 NS Peak aerobic capacity (mlOz/kg/min)(n = 8) 17*7 21 k5 21 +8 0.06 Hospitalizations (n = 13) 1.1 k0.9 0.5 0.9 0 0.002

~ ~ ~~ ~ The changes, initial to 6 months, 6 months to 12 months, were not separately statIstIcally significant. Abhrtwatront ACE = angiotensm-convertingenzyme, NS = not ygficant 902 Clin. Cardiol. Vol. 21, December 1998

TABLEI11 Retrospective 12-month echocardiographic changes on 85 patients in the presence or absence of atenolol

0 Atenolol - Atenolol n=36 n=49 pValue Ejectionfraction(%) 015214 0llil3 NS Left ventricular end-diastolic diameter (cm) -0.42 I -0.2 20.8 NS Mitral regurgitation FIG.1 All 13 patients underwent initial, 6-month, and 12-month (0 =none,4 =severe) -0.9 i 1.4 -0.8 i 1.2 NS follow-up echocardiography. 6 Months: ACE inhibitor-nitrates alone; I? months: beta blocker added. The p value (6-12 months) Lisinopril dose: 70 2 16 mg/day; isosorbide dinitrate dose: ’248 ~f:163 was not significant. ACE = angiotensin-concerting enzyme, LV = mg/day; atenolol dose: 54 i33 mg/day. left ventricular. = Initial, = 6 months, = 12 months. Abbreviurion: NS = not significant.

Impact of High-Dose Angiotensin-Converting Enzyme It is likely that the failure to demonstrate additional changes Inhibitor-Nitrates with atenolol is due to the clinical and echocardiographic im- provements already achieved by the group. That the cohort We have previously shown that high-dose ACE inhibitor does not represent a ‘‘responder’’ selection bias is demonstrat- and nitrate therapy may not only stabilize but actually reverse ed by comparable findings in the larger retrospective cohort the heart failure remodeling process.I6 Correspondingly,there comprising all patients on high-dose ACE inhibitor-nitrates. was a significant improvement in left ventricular ejection frac- It would, however, appear that phamiacologic approaches tion over 6 months in response to uptitrated ACE inhibitor- to reverse ventricular remodeling, albeit complementary. may nitrate therapy alone, associated with a significant lessening of not be additive. Undoubtedly, the tissue remodeling process the seventy of functional mitral regurgitati~n.’~-’~ may induce a number of irreversible changes. Alternatively, Although moderate dose ACE inhibition (15-20 mg/day even beta-receptor blockade in conjunction with high-dose of ena1aprilP s, improves symptomatic status and survival ACE inhibitors and nitrates may not yet comprehensively of patients with mild to severe heart failure,”’ this dosage control all the auto- and paracrine neurohormonal and cy- range suffices only to stabilize left ventricular systolic dys- tokine tissue effects of heart fail~re.~~J~Whether nonselec- lunction.*%‘)%2o It appears that at the higher dosages, pharma- tive beta blockers or newer beta blockers with vasodilator cologic mechanisms over and above hemodynamic unload- properties offer an advantage over earlier selective beta- 1 re- ing efYects*’-” may be playing a role. The expected reduc- ceptor blockers is currently being studied. Conceivably, addi- tion in tissue angiotensin I1 production and endothelin ex- tional therapy targeting inflammatory cytokines, angiotensin pression,’l%25 enhanced bradykinin-mediated generation of II, and/or endothelin- 1 receptors might further enhance the re- prostaglandin and nitric oxide would impact favorably on versal process. the regression of myocyte hypertrophy, on interstitial fibro- sis, and myocyte metabolism.2”30 Study Limitations

Beta-Receptor Blocker Addition to High-Dose Angiotensin- Our study is not a randomized, placebo-controlled ma1 for Converting Enzyme Inhibitor-Nitrates the addition of beta-blocker therapy over and above high-dose lisinopril-nitrate therapy. The number of patients studied is Beta-adrenergic blockade may improve myocardial metab- small, and the observed changes at 12 months may actually re- olism in heart failure while protecting the myocardium from flect the continued response to ACE inhibitors-nitrates alone excessive catecholamine exposure.]’. 14, 31-34 The postulated rather than the effect of added beta-blocker therapy. mechanisms of beta-blocker therapy would thus further com- On the other hand, there was a trend toward improvement plement and potentially enhance the expected effects of ACE seen with beta blockade, and a large cohort may have shown inhibitor-nitrate therapy. A reversal of heart failure remodeling greater benefit. “Early” versus “late” addition of beta block- has been observed in numerous studies of beta-receptor block- ade, or a nonselective third generation beta-receptor blocker ade added to the lower dose range of ACE inhibiti~n.’~’~ may have had different outcomes. However, when added to established high-dose ACE inhib- itor-nitrates,atenolol therapy accomplished no further signifi- cant improvement in either functional status or left ventricular Conclusion function. Neither did the presence of beta-receptor blockade significantly affect left ventricular recovery in the larger retro- We found that high-dose ACE inhibitor-nitrate therapy less- spective reference cohort. ened clinical heart failure-related symptoms and improved T.B. Levine rf 1~1.:Beta blocker addition to high dose ACE inhibitor-nitrates 903 functional status and left ventricular function. 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