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J Am Coll Cardiol, 2001; 38:1675-1684 © 2001 by the American College of Cardiology Foundation |
a Fondazione "Salvatore Maugeri," Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Scientifico di Montescano, Pavia, Italy
Manuscript received April 18, 2001; revised manuscript received July 20, 2001, accepted August 15, 2001.
* Reprint requests and correspondence: Dr. Soccorso Capomolla, Department of Cardiology, Montescano Medical Center, Via per Montescano, 27040 Montescano, Pavia, Italy
scapomolla{at}fsm.it
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Abstract |
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The goals of this study were: 1) to assess the predictive value of baseline mitral flow pattern (MFP) and its changes after loading manipulations as regards tolerance to and effectiveness of beta-adrenergic blocking agent treatment in patients with chronic heart failure (CHF); and 2) to analyze the prognostic implications of chronic MFP modifications after beta-blocker treatment.
BACKGROUND
In patients with CHF, carvedilol therapy induces clinical and hemodynamic improvements. Individual management, clinical effectiveness and prognostic implications, however, remain unclear. The MFP changes induced by loading manipulations provide independent prognostic information.
METHODS
Echo-Doppler was performed at baseline and after loading manipulations in 116 consecutive patients with CHF (left ventricular ejection fraction: 25 ± 7%); 54 patients with a baseline restrictive MFP were given nitroprusside infusion; 62 patients with a baseline nonrestrictive MFP performed passive leg lifting. According to changes in MFP, we identified four groups: 17 with irreversible restrictive MFP (Irr-rMFP), 37 with reversible restrictive MFP (Rev-rMFP), 12 with unstable nonrestrictive MFP (Un-nrMFP) and 50 with stable nonrestrictive MFP (Sta-nrMFP). Carvedilol therapy (44 ± 27 mg) was administered blind to results of loading maneuvers. After six months, MFP was reassessed and patients reclassified according to chronic MFP changes. During follow-up, tolerance to and effectiveness of treatment and major cardiac events (death, readmission and urgent transplantation) were considered.
RESULTS
Changes of MFP after loading manipulations were more accurate than baseline MFP in predicting both tolerance to (p < 0.01) and effectiveness of (p < 0.05) carvedilol. After 26 ± 14 months of follow-up, cardiac events had occurred in 23/102 patients (23%). The event rate in patients with chronic Irr-rMFP or Un-nrMFP was markedly higher than it was in those with Rev-rMFP or Sta-nrMFP.
CONCLUSIONS
In our patients, tolerance to and effectiveness of carvedilol was predicted better by echo-Doppler MFP changes after loading manipulations than by baseline MFP. Chronic changes of MFP after therapy are strong predictors of major cardiac events.
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Available data show that beta-adrenergic blocking agents improve LV performance and symptoms, slow the progression of CHF and reduce morbidity and mortality (15–18). Different mechanisms have been suggested to explain how these drugs induce beneficial effects on the remodeling process (19,20). However, a variable percentage of subjects are intolerant, and it is still unknown whether the same administration protocol should be followed for all patients or whether individualized treatment strategies should be used. Whether the analysis of the MFP could help to manage the titration therapy of beta-blockers and predict their tolerance and effectiveness has not yet been determined.
Accordingly, this study was performed to: 1) assess the predictive value of baseline MFP as regards tolerance to and effectiveness of beta-blocker treatment in a population of patients with CHF; 2) evaluate whether acute changes of MFP induced by loading manipulations may increase predictive accuracy, and 3) analyze the prognostic implications of chronic MFP modifications after treatment with beta-blockers.
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Methods |
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Patients who fulfilled the following criteria were entered into the study: clinical stability >3 months; optimized oral therapy; technically adequate Doppler echocardiographic recordings, sinus rhythm on electrocardiogram; absence of cardiac prosthetic valves or of any important regional myocardial ischemia suitable for revascularization and a clinical history without the normal contraindications to beta-blockers. The patients were enrolled in the study after having given informed consent.
Clinical, hemodynamic and Doppler echocardiographic characteristics of the group, as well as therapeutic regimens, are reported in Table 1.
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Study protocol |
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Baseline evaluation.
Clinical and functional determinations
All patients underwent a complete physical examination and New York Heart Association (NYHA) functional class classification. Maximal exercise capacity was evaluated during a symptom-limited cyclette exercise test by measurements of peak oxygen consumption (VO2) (Medical Graphics Corp., 2001 analyzer).
Echocardiographic measurements
Echocardiographic studies were performed using a Hewlett Packard 5500 ultrasound system with 2.5 MHz and 3.5 MHz transducers. Doppler echocardiographic examinations were performed at baseline and after six months. All images were recorded on videotape and subsequently analyzed using the software packages built into the ultrasound system. Doppler velocity curves were recorded at a sweep velocity of 100 cm/s.
Left ventricular end-systolic and end-diastolic volumes and dimensions and LVEF were assessed by apical four-chamber views using the modified Simpson’s rule (21). Images were accepted for analysis according to the guidelines proposed by Gordon when at least 80% of endocardium was seen (22).
Mitral flow velocity was obtained from a two-dimensional apical window with a pulsed wave technique by placing the sample volume between the tips of the mitral leaflets. The calculation of proximal accelerating flow was performed using the method proposed by Bargiggia et al. (23). The following parameters were calculated as averages over five consecutive measurements: maximal velocity of early (E) and late (A) diastolic filling, deceleration time (DT) of early diastolic filling and the ratio of maximal early to maximal late diastolic filling velocities (E/A) (24). We identified, by our experience, two MFPs: 1) a restrictive pattern when E/A was >1 and DT was 
130, and 2) a nonrestrictive pattern when E/A was 1 or E/A was >1 and DT was >130. According to these patterns, patients were classified as, respectively, restrictive and nonrestrictive.
Loading manipulations. After recording MFP at baseline, loading manipulations were performed. Specifically, in the patients with restrictive MFP, nitroprusside was administered by intravenous pump infusion at incremental doses of 0.5 µg/kg per min every 5 min until a systolic arterial pressure <80 mm Hg or pulmonary wedge pressure <15 mm Hg or patient’s discomfort were observed. At maximal infusion dose in steady state condition, echo-Doppler examinations were again carried out. In the patients who had a nonrestrictive MFP at baseline, the echo-Doppler examinations were performed after passive lifting of the legs to 45°. The MFP after both loading manipulations was identified according to the same criteria as those used at baseline.
The patients were then classified into four subgroups according to baseline and acute response to loading manipulations: 1) patients with irreversible restrictive MFP (Irr-rMFP) (a baseline restrictive mitral flow that remained restrictive after nitroprusside); 2) patients with reversible restrictive MFP (Rev-rMFP) (a baseline restrictive mitral flow that was restored to normal or pseudonormal MFP after nitroprusside infusion); 3) patients with unstable nonrestrictive MFP (Un-nrMFP) (a baseline nonrestrictive MFP that became restrictive after passive leg lifting); 4) patients with stable nonrestrictive MFP (Sta-nrMFP) (a baseline nonrestrictive MFP that remained so after passive leg lifting).
Management of beta-blocker titration. Carvedilol therapy was administered to all patients according to current guidelines. The titration of this beta-blocker was performed by a physician blinded to the results of the echo-Doppler examinations. This phase could be continued after hospital discharge in an outpatient setting. During the titration, supplementary examinations (chest X-ray, echo-Doppler and blood tests) were seldom carried out and therapeutic variations (increase of diuretics or angiotensin-converting enzyme inhibitor modifications) made accordingly. Patients were defined "tolerant" when they had tolerated and completed the whole phase of titration.
Follow-up. All patients were followed-up with programmed clinical and functional evaluations, including MFP assessment, every six months in our hospital. The effectiveness of beta-blocker therapy after six months treatment was examined from both clinical and instrumental points of view. In particular, we considered the treatment "clinically effective" when it improved NYHA functional class and decreased cardiac events (cardiac mortality or urgent heart transplantation or readmission for congestive heart failure). Conversely, we considered the treatment "instrumentally effective" when it was accompanied by a greater improvement in LV performance than that expected from chance alone due to intra- and interobserver variability (25). In particular, LVEF, DT and mitral regurgitation were considered improved if the change observed after six months was respectively >4%, >11 ms and <–4 mm (proximal isovelocity surface area [PISA]).
In the period between two evaluations, the clinical status of patients was monitored by intermittent telephone contacts with the patient and his physician and by mailed questionnaires.
Statistical analysis. Between-group comparisons of baseline clinical and functional parameters were performed by one-way analysis of variance for continuous variables and by the chi-square test for categorical variables. Multiple comparisons were performed by the Tukey’s studentized range test. Multivariate logistic regression analysis was used to assess the prognostic value of baseline MFP in predicting 1) tolerance to, and 2) effectiveness of beta-blocker therapy. The same analysis was repeated using as predictor the MFP change after loading manipulations, and the two predictive models were compared by the rescaled generalized coefficient of determination (range of variation 0 to 1) (26) and by the area under the receiver operator characteristic curves (AUC) (27). Age, gender, etiology, NYHA class, LVEF and peak VO2 were used in model building as adjusting covariates. Covariance analysis was used to assess the association between MFP and beta-blocker dosage at the end of the titration phase. For the purpose of prognostic evaluation, chronic changes of MFP after six months of beta-blocker treatment were considered as predictors of the combined outcome of cardiac mortality plus urgent heart transplantation plus readmission for congestive heart failure. Event-free distribution functions were estimated by the Kaplan-Meier method. The association between predictor variables and outcome was assessed by the Cox proportional hazards regression model. All patients who died from noncardiac causes and those who underwent elective cardiac transplantation were considered as censored observations. Prognostic information was expressed as relative risk with 95% confidence interval (CI). Descriptive statistics are presented as mean ± SD. A p value of <0.05 was considered as statistically significant.
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Results |
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The two loading manipulations to evaluate diastolic reserve (sodium nitroprusside test in the patients with a restrictive MFP and passive leg lifting in the other patients) were well tolerated without adverse events. After the sodium nitroprusside test 17/54 (31%) patients did not change their MFP and were allocated to subgroup 1 (Irr-rMFP). In the remaining 37/54 (69%) patients, the MFP reverted to a nonrestrictive form, and these patients were allocated to subgroup 2 (Rev-rMFP). Clinical and instrumental findings were similar in the two subgroups (Table 2), and no differences were found in the maximal dose of nitroprusside infusion (1.3 ± 1.5 µg/kg per min vs. 1.1 ± 1.3 µg/kg per min, p = 0.7). After the leg-lifting maneuver, 12/62 (19%) patients developed a restrictive MFP and were allocated to subgroup 3 (Un-nrMFP). The remaining 50/62 (81%) patients maintained a nonrestrictive MFP and were allocated to subgroup 4 (Sta-nrMFP). Overall, MFP changed in 49/116 (42%) patients after strategies to assess the diastolic reserve.
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Figure 1 shows the titration profile according to baseline MFP and its change after loading manipulations. The management of beta-blocker titration was more complex in the groups with a restrictive MFP at baseline than in the groups with a nonrestrictive MFP. Patients with a baseline restrictive MFP had a greater number of titration interruptions compared with patients with a nonrestrictive pattern (20% vs. 5%, p = 0.02). Among restrictive patients, those with an irreversible pattern after loading manipulations had a much higher treatment interruption rate compared with those with a reversible pattern (47% vs. 8%, p = 0.001). Conversely, among nonrestrictive patients, those with a stable pattern after loading manipulations had a much lower treatment interruption rate compared with those with an unstable pattern (2% vs. 17%, p = 0.03). Patients who had a baseline restrictive MFP were more frequently submitted to additional examinations and therapeutic variations than those with a nonrestrictive pattern (46% vs. 19% and 44% vs. 16%, p = 0.002 and p = 0.001, respectively). In the subgroup with Irr-rMFP, 88% required additional examinations and 82% therapeutic variations, while, in the subgroup with Rev-rMFP, only 27% needed additional examinations, and another 27% had therapeutic variations (p < 0.001 for both comparisons). Among nonrestrictive patients, only 10% of those with a stable pattern after loading manipulations required additional examinations, and only 8% needed therapeutic variations, whereas the same procedures were required, respectively, in 58% and 50% of unstable patients (p < 0.001 for both comparisons).
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Baseline MFP and its changes induced by loading manipulations were also significantly associated with beta-blocker dosage at the end of the titration phase (p < 0.001). All potential covariates were nonsignificant (p > 0.2). Corresponding coefficients of determination for the two models were 0.1 and 0.3, respectively.
Effectiveness of beta-blocker treatment. At six months, patients showed better NYHA functional class than they did at baseline (NYHA I to II: 91% vs. 74%, NYHA III to IV: 9% vs. 26%, p < 0.001). An improvement in LVEF, DT and mitral regurgitation according to the study criteria (see Methods section) was observed, respectively, in 62%, 48% and 66% of the patients. Of the patients with a baseline restrictive MFP, 31/43 (72%) moved to a nonrestrictive MFP (chronic Rev-rMFP) and 12/43 (28%) did not change MFP (chronic Irr-rMFP). Of the 31 patients, 30 (97%) had a Rev-rMFP after loading manipulations at the start of the study. Only one patient with an Irr-rMFP at the start of the study had changed to having a nonrestrictive MFP at six months. Of the patients with a baseline nonrestrictive MFP, 49/59 (83%) maintained a nonrestrictive MFP (chronic Sta-nrMFP), and 10 (17%) worsened and moved to a restrictive MFP (chronic Un-nrMFP). Six (60%) of the latter had a Un-nrMFP after loading manipulations.
The association between either baseline MFP or its acute change after loading manipulations and improvement in LVEF, DT and mitral regurgitation after beta-blocker treatment is presented in Table 4. Baseline MFP did not provide any predictive information on the improvement in LV performance and mitral regurgitation after beta-blocker treatment. In contrast, the acute change in MFP after loading manipulations showed a highly significant association with all three aspects of beta-blocker treatment effectiveness. It is worth emphasizing, in particular, that the presence of a restrictive irreversible or nonrestrictive unstable pattern was a significant predictor of improvement in LV performance and mitral regurgitation but not of improvement in DT, whereas the presence of a restrictive reversible pattern acted in the opposite direction.
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Discussion |
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In our experience carvedilol was well tolerated by patients with heart failure; only 12% of patients had to be withdrawn from the titration phase due to adverse events. These data are consistent with the results of other studies that showed a variable degree of intolerance (15,19,29). The rate of withdrawal increases when the patients treated have severe heart failure. Krum et al. (30) reported 49.5% of intolerance in patients in NYHA functional class IV. In the study by McDonald et al. (31), 43% of patients who were in NYHA functional class IV experienced adverse events. However, in about one-third of patients initially intolerant to carvedilol, the drug could be reintroduced, and it produced clinical benefits. This evidence gives rise to two important considerations: 1) the titration phase of beta-blocker therapy can be affected by adverse events that are time and cost-consuming, 2) despite the rate of intolerance to beta-blockers in patients with severe heart failure, in selected subgroups carvedilol is a useful adjunctive therapy. Our results showed that MFPs after loading manipulations were more accurate than baseline MFP and NYHA functional class in identifying patients who required different management of carvedilol titration. In particular, we demonstrated that 47% of patients who had an Irr-rMFP developed adverse events requiring consequent therapy interruption; the remaining subgroup tolerated treatment, but titration management was complex, and, later, no clinical benefits were demonstrable. In contrast, all those who had a Sta-nrMFP tolerated carvedilol; management of the titration was uncomplicated, and at six months the patients had more clinical benefits. Patients with changes of MFP after loading manipulations were in between these two extremes. In particular, patients with a Un-nrMFP showed a significantly more complex titration and tended to have more likelihood of carvedilol interruption than patients with Rev-rMFP after acute nitroprusside infusion. In contrast, this last group of patients exhibited better clinical improvement. The improvement of LV performance after chronic therapy with carvedilol was concordant with the demonstrated cardiovascular reserve during acute loading manipulations. Ventricular remodeling and abnormal neurohormonal activity are time-dependent maladaptive processes in response to myocardial injury (6). Previous studies have shown how indexes of MFP are determined by complex interactions of intrinsic characteristics of the heart such as relaxation and chamber stiffness and extrinsic factors such as loading manipulations (32–34). Baseline MFP and its changes after loading manipulations may represent the several steps of LV remodeling. Precisely, in our experience, patients with a baseline nonrestrictive MFP had uncomplicated titration of carvedilol and derived most clinical benefits. In this subgroup, abnormal relaxation was the predominant factor conditioning ventricular filling with a concomitant compensatory increase of the atrial contribution to filling. It is likely that carvedilol in this subgroup improved intrinsic ventricular properties such as abnormal relaxation and prevented, by blockade of catecholamine actions, the remodeling process (35). However, after leg lifting, 19% of these patients acquired a restrictive filling pattern. It is likely that abnormalities of relaxation coexist with those of chamber stiffness. Preload manipulation exposed changes in chamber stiffness, which could have caused different titration of and clinical benefits from carvedilol administration. At the other extreme are the subgroups of patients with a baseline restrictive MFP who had a more complex titration management and less clinical benefits from carvedilol titration than those with a nonrestrictive MFP. However, after nitroprusside infusion, 69% of these patients acquired a nonrestrictive MFP. It is likely that LV remodeling had not affected chamber stiffness in these patients but that they had unfavorable loading conditions. In fact, nitroprusside, by preload, afterload and mitral regurgitation reductions shifts the LV pressure/volume curve leftward and downward with an improvement of early diastolic filling (decrease of peak velocity, increase of DT) and increases the atrial contribution to filling (36). Despite the same dosage of nitroprusside, a subgroup of patients maintained a restrictive MFP. This peripheral pooling effect of nitroprusside unmasked an LV with increased chamber stiffness. In this setting, the clinical surrogates were a complex titration management and few clinical benefits. Overall, in 49/116 (42%) the patients’ baseline MFP or NYHA functional class was not able to predict the response to or the clinical effects of carvedilol administration. Changes of MFP after loading manipulations, by revealing operative chamber stiffness, restored the power of MFP to identify patients with different responses to carvedilol administration.
Chronic changes of MFP after beta-blocker therapy: trends and prognostic information. Another interesting finding of this study is that, in patients with congestive heart failure receiving chronic treatment with carvedilol, changes of MFP identified by echo-Doppler were strongly related with functional effects and gave important prognostic information. Stevenson et al. (37) showed how forced unloading therapy could induce marked clinical benefit. Although we did not have a control group, in our previous experience, long-term echo-Doppler monitoring of MFP in patients with CHF and optimized therapy showed that, at six months, the MFP moved from restrictive to nonrestrictive in 28% and vice versa in 20% of patients (28). In contrast, in patients who received carvedilol treatment, after six months MFP shifted from restrictive to nonrestrictive in 72% and vice versa in 17% of patients. These findings support the role of beta-blockers in removing unfavorable loading conditions and influencing LV remodeling. Previous studies showed that a restrictive MFP was associated with increased mortality in patients with CHF (9,10). Our study confirms these findings and extends them, showing that, after titration, the changes of MFP are strongly associated with event rates; so, in patients who moved after titration from a restrictive MFP to a nonrestrictive MFP, the event rate decreased from 58% to 16%. Conversely, in patients who moved from a nonrestrictive to a restrictive MFP, the event rate increased from 6% to 80%. In addition, 15/23 (65%) hard events occurred in patients who showed a restrictive MFP at six months (Table 5). This has independent prognostic value by Cox analysis.
Study limitations. The greatest limitation of this study is that its results cannot be applied to patients with atrial arrhythmias, a pacemaker or a prosthetic mitral valve. Although echocardiographic measurements can be affected by poor image quality or by interobserver variability, using a cutoff value of reproducibility to evaluate a result as significant minimized the likelihood of these errors occurring. Furthermore, potential abnormalities should have been distributed evenly between the groups and, thus, would not be expected to have altered the significance of the changes found. The diastolic alterations were evaluated using Doppler variables, which may be affected by different factors (loading conditions, heart rate) and cannot, therefore, be conclusive about intrinsic diastolic function and the effects of carvedilol on diastolic properties (relaxation rate and chamber stiffness). The chronic evaluation at six months was an arbitrary choice determined by the organization of follow-ups in our division. In effect, the chronic control could be performed three months after the end of the titration phase.
Conclusions. This study investigates the relationship between LV echo-Doppler monitoring and safety and efficacy of long-term carvedilol therapy in patients with CHF. Recent evidence showed that beta-blockers reduce mortality and improve quality-of-life in patients with heart failure. Patients who can profit from this effective and inexpensive treatment are increasing; however, it has recently been demonstrated that, in patients with CHF, the individual response to beta-blocker therapy is highly variable in terms of tolerance and efficacy, and most patients with severe heart failure may be excluded from benefits of this useful therapy. Our study shows that MFP and its changes after loading manipulations may identify patients requiring different clinical management during beta-blocker titration and deriving different chronic benefits. Furthermore, echo-Doppler MFP evaluated during chronic beta-blocker treatment provides a strong independent contribution to the assessment of the risk of hard cardiac events. We believe that echo-Doppler monitoring of mitral flow at baseline and during loading manipulations is an operative tool for managing beta-blocker therapy in patients with CHF and for redefining therapeutic strategies, including heart transplantation, in those patients on chronic beta-blocker therapy.
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