European Heart Journal Supplements (2004) 6 (Supplement H), H61–H66

Treatment of heart failure with preserved systolic function: a review of the evidence Karen Hogg, John J.V. McMurray* Department of Cardiology, Western Infirmary, Glasgow, UK

KEYWORDS Candesartan; Clinical trials; Heart failure; Left-ventricular systolic function

Introduction Heart failure (HF) is now fully recognised as a major public health problem 1,2 . It has been estimated that there are nearly 23 million people with heart failure worldwide 1 . The escalating public health problem of HF in industrialised countries is due to the ageing population. In the UK the overall prevalence of HF has been estimated to be 3–20 cases per 1000 population, rising to >100 cases per 1000 population in those aged 65 years and older 3 . HF is a huge burden to patients in terms of mortality and morbidity, but is also a considerable financial cost to the National Health * Correspondence: Professor JJV McMurray. Department of Cardiology, Western Infirmary, Glasgow G11 6NT, UK. Tel.: +44-141-211-1838; fax: +44-141-211-2252. E-mail address: [email protected] (J.J.V. McMurray).

0169-5002/$ – see front matter

Service (NHS), accounting for approximately 2% of the entire NHS budget in the UK 3 , and 15–40 billion dollars in the USA 4,5 . Great advances have been made in terms of the epidemiology and treatment of this kind of heart failure. Over the past decade heart failure with preserved systolic function (HF-PSF) has become a clinical entity in its own right. Cohort studies of hospitalised patients suggest that a third to a half of patients thought to have clinical heart failure have preserved left-ventricular systolic function 6–13 . Various studies have now reported that patients with this type of heart failure have a mortality rate which is lower than heart failure with reduced systolic function (HF-RSF) but is still high overall 14–17 . In addition, hospital admission (and re-admission) is common and length of stay in hospital is comparable to that with HF-RSF 9,18,19 . What is still not clear, however, is how best to treat this group of

© 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.

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The importance of heart failure with preserved systolic function (HF-PSF) has been increasingly recognised during the last decade. However, until recently there were no large, randomised, controlled clinical outcome trials in patients with this condition. Indeed, the best evidence of symptom improvement came from two very small studies with the rate-limiting calcium-channel blocker verapamil, in a total of fewer than 50 patients. The largest outcome trial was an ancillary study (with about 900 patients) of the Digitalis Investigators Group (DIG) trial, in which digoxin was reported to have a proportionately similar effect on morbidity to that seen in patients with reduced systolic function. Recently, the CHARM-Preserved study randomised over 3000 patients to placebo or candesartan. There was a trend to a reduction in cardiovascular death or hospitalisation for heart failure with candesartan (333 vs. 366 patients, unadjusted p = 0.118; co-variate adjusted p = 0.051), and clear reductions in the proportion of patients admitted (by 15% from 270 to 230 patients, p = 0.017) and the total number of hospital admissions for worsening heart failure (by 29% from 566 to 402 admissions, p = 0.014). Overall the results of the CHARM Programme showed that candesartan exerted a favourable effect across a broad spectrum of patients with heart failure, irrespective of left-ventricular function, co-morbidity, symptomatic class or concomitant treatment. © 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.

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patients. One problem is that, until recently, there have been few large randomised, controlled trials in patients with HF-PSF 20 . However, with the CHARM results now available, and other trials in progress, the situation is improving.

Studies with symptoms/functional capacity as endpoints Heart-rate-limiting calcium-channel blockers

(2.16±0.48 EDV/s). There was a suggestion of a carryover effect on the PFR in those patients receiving verapamil before placebo treatment. The average systolic blood pressure did not differ significantly between the two groups. However, verapamil did lower diastolic blood pressure (baseline 84±6 mmHg, 79±6 mmHg during verapamil treatment, P < 0.05; placebo 82±8 mmHg at the end of the placebo period). Verapamil also reduced mean heart rate (baseline 79±11 bpm, verapamil 71±11 bpm, P < 0.05; placebo 78±9 bpm). Verapamil did not reduce peak heart rate or systolic blood pressure during exercise. Treatment with verapamil improved the patients’ symptoms as indicated by a reduction in the CHF scores from a baseline of 6.7±1.7 to 3.8±1.6 following treatment with verapamil. With placebo treatment, the CHF score increased (worsened) to 6.1±1.9 (P < 0.01). Verapamil improved exercise tolerance in the 12 patients who were able to exercise. Baseline time was 10.7±3.4 min and this increased to 13.9±4.3 min (P < 0.05) with verapamil. The between-treatment-group comparison was also significant (P < 0.01). Very similar improvements in symptoms and exercise tolerance were also reported by Hung et al. 23 in an almost identical study. In that study treatment with verapamil improved the CHF score from 5.5 to 3.5 and increased exercise tolerance from 7.4 min to 8.3 min on treadmill testing 23 . Angiotensin-converting-enzyme (ACE) inhibitors Angiotensin II is thought to play a causal role in left-ventricular hypertrophy (LVH), and reduces leftventricular (LV) relaxation and increases LV stiffness. ACE inhibitors are known to reduce LVH and to improve diastolic filling. In patients with prior myocardial infarction, an ACE inhibitor is of benefit in reducing the risk of future vascular events. Philbin et al. 24 compared outcome data from patients with ‘diastolic heart failure’ receiving and not receiving ACE inhibitors, and suggested that treatment may reduce heart-failure hospitalisation. As the study was non-randomised, firm conclusions cannot be drawn. Aronow et al. 25 compared treatment with enalapril to no treatment with enalapril in 21 elderly patients (mean age 80 yrs) with NYHA class-III HF associated with prior Q-wave myocardial infarction but with preserved LV systolic function (EF > 0.50). All patients in this study were in sinus rhythm and were treated with frusemide but no other cardiac medication. The target dose of enalapril was 10 mg twice daily (by week 5 of titration). A chest X-ray, echocardiogram and modified Bruce treadmill exercise test were performed at baseline and repeated following 3 months of treatment. Cardiothoracic ratio, ejection fraction, NYHA class and exercise time all improved in the enalapril group but not in the control (no enalapril) group. Leftventricular mass fell after enalapril treatment (from 313±43 g to 280±46 g, P < 0.001) but not in the control group (306±51 g to 309±55 g). Peak mitral Doppler E/A ratio increased with enalapril from 0.6±0.1 to

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Conceptually, the pharmacology of this class of drugs which slow heart rate and reduce myocardial contractility is attractive in a therapeutic sense in patients with HF-PSF who in many (if not most) cases will have diastolic dysfunction 21 . There have been two small, controlled, randomised, cross-over, blinded comparisons of placebo and verapamil 22,23 . Setaro et al. 22 studied 22 patients with clinical heart failure but preserved systolic function for >3 months (ejection fraction >0.45) but an abnormal peak filling time (PFR) >2.5 end-diastolic volume (EDV)/s 22 . Exclusion criteria included obstructive airways disease, valve disease, hypertrophic obstructive cardiomyopathy and symptomatic or occult myocardial ischaemia. The authors did not mention whether atrial fibrillation (AF) was an exclusion criterion. Baseline assessments were made of symptoms, exercise tolerance and left-ventricular systolic and diastolic function using a Chronic Heart Failure (CHF) score, a treadmill exercise test (modified Naughton protocol) and cardiac radionuclide studies, respectively. Baseline blood pressure and heart rate were also recorded. The diuretic dose was kept constant, but digoxin was withdrawn 7 days before randomised treatment was started. Withdrawal of digoxin can be associated with a clinical deterioration. However, the authors did not mention the proportion of patients receiving digoxin at baseline and how many of these were randomised to verapamil or placebo. The initial verapamil dose was 80 mg three times daily for 1 week and if tolerated this was increased to 120 mg three times daily. If the initial dose was not tolerated then it could be reduced to 80 mg twice daily. The mean daily dose of verapamil taken was 256 mg (range 160–360 mg). Following 2 weeks of randomised treatment, the patients were re-evaluated by a blinded investigator; this assessment included clinical examination, CHF scoring, exercise testing and radionuclide scanning. Following a 4-day wash-out period, patients were crossed over to the second treatment period with a similar re-evaluation. Twenty of the 22 patients completed the study: one did not comply and the other developed a supraventricular tachycardia requiring openlabel verapamil treatment. Verapamil had no effect on ejection fraction (baseline 60±9%, placebo 60±10%, verapamil 62±8%, respectively). PFR increased from baseline with verapamil (1.85±0.45 EDV/s vs. 2.29±0.54 EDV/s, P < 0.05) but did not change significantly with placebo treatment

K. Hogg, J.J.V. McMurray

Treatment of heart failure with preserved systolic function: a review of the evidence

0.7±0.1 (P < 0.001), but not in the control group (0.6±0.2 to 0.6±0.2). Resting systolic and diastolic blood pressure fell during enalapril treatment, but not in the control group. These findings, whilst encouraging, do not support routine use of ACE inhibitors in patients with HF-PSF. A very small number of patients were studied, within-group rather than between-group differences were described, and the study had an open design 25 . Angiotensin-receptor blockers (ARBs)

Studies examining the effect of treatment on morbidity/mortality

Two-dimensional echocardiography was carried out at baseline, before randomisation, and again after one year of treatment. LVEF and left-ventricular mass were measured by a blinded echocardiographer. Mortality and the composite endpoint of death or non-fatal myocardial infarction (MI) were also assessed by intention to treat. Propranolol was discontinued by 11 of 79 patients (14%) because of adverse effects (worsening HF in 7 and hypotension in 14). Following a year of treatment, there was a significant increase in LVEF and a greater reduction in leftventricular mass in the propranolol group. Treatment with propranolol was associated with a lower mortality (44/79 [56%] of the propranolol patients died compared to 60/79 [76%] in the no-propranolol group, P = 0.007) and a lower risk of death or non-fatal MI (47 [59%] vs. 65 [82%], respectively, P = 0.002). Although these results are favourable they are interpreted on the background of the lack of a placebo control group and a highly selected group of patients. Also, the beneficial action of b-blockers in post-MI patients is well recognised already, and so the results of this study may have been anticipated. Similarly, the composite death or MI endpoint, while important, is perhaps not the most relevant one in the more general population of patients with HF-PSF. The role of b-blockers in HF-PSF will, hopefully, be clarified by the results of the Study of Effects of Nebivolol Intervention on Outcomes and Re-hospitalisation in Seniors with heart failure (SENIORS) 34 . SENIORS is a large double-blind, prospective, randomised controlled morbidity/mortality trial, comparing placebo to nebivolol in approximately 2000 patients with HF aged 70 years 34 . The inclusion criteria require either a documented LVEF  0.35 or a hospital admission with HF within 12 months. It is expected that about a third of the patients in SENIORS will have HF-PSF. The primary endpoint in this trial is death or cardiovascular hospitalisation.

b-blockers As with verapamil, b-blockers might be expected to be beneficial in HF-PSF; since they reduce the heart rate their negative inotropic properties should also improve diastolic function. Aronow et al. 33 studied the effect of propranolol in an open study on 158 elderly patients (62 yr) with heart failure and preserved left-ventricular systolic function (LVEF  0.40). In contrast to the study of Setaro et al. 22 with verapamil, there were several important differences in enrolment criteria: patients with coronary heart disease were not excluded and, in fact, all had a prior Q-wave infarction. All patients in this study were receiving baseline diuretic and b-blocker therapy. A third of patients were in atrial fibrillation and the study had an open design. In total, 79 patients were randomised to receive propranolol and 79 did not receive propranolol. The follow-up period was 32 months. The initial dose of propranolol was 10 mg per day. The dose was increased by 10-mg increments at 10-day intervals until the target dose of 30 mg three times daily was reached.

ACE inhibitors ACE inhibitors should be of value in HF-PSF as these patients often have hypertension, LVH, diabetes and coronary artery disease. Studies such as HOPE and EUROPA with ACE inhibition, and LIFE, SCOPE, RENAAL, IDNT, Val-Heft, CHARM and VALIANT with angiotensinreceptor blockers suggest that interruption of the renin–aldosterone–angiotensin system (RAAS) will be of benefit. The Perindopril for Elderly People with Chronic Heart Failure (PEP-CHF) study has recruited around 1000 patients aged >70 yrs with HF and no major leftventricular systolic dysfunction (LVEF < 0.40 or wallmotion index 0.45 were randomised to receive placebo (n = 496) or digoxin (n = 492). By comparison, 3403 patients with HF and a LVEF  0.45 were randomised to placebo and 3397 to digoxin in the main trial. There were 116 deaths (23.4%) in the placebo group and 115 deaths (23.4%) in the digoxin group in the ancillary trial. For the combined endpoint of death or hospitalisation, the results in the ancillary trial (risk ratio with digoxin 0.82, 95% CI: 0.63–1.07) were consistent with the findings in the main trial (risk ratio 0.85, 95% CI: 0.79–0.91; P < 0.001). Unfortunately no further information on outcome in the preserved-LVEF ancillary trial is available. The findings of the DIG trial are supported, to some extent, by those of a trial primarily designed to evaluate xamoterol 39 . This study compared the effects of placebo, xamoterol and digoxin on symptoms, signs and exercise capacity in patients with a spectrum of HF. LVEF was not reported but 80–90% of patients were in NYHA Class I or II, about half had angina, only a quarter were taking diuretics, and just over a third had radiological cardiomegaly (a cardiothoracic ratio of 0.52). Thus, it was highly likely that many of these patients had ‘diastolic heart failure’. Digoxin significantly improved breathlessness, tiredness, chest pain, oedema and basal crepitations 39 . Digoxin also reduced weight and cardiothoracic ratio more than placebo.

It is with this group of drugs that the unsatisfactory state of affairs regarding adequate clinical trials in patients with HF-PSF has begun to improve. The Candesartan in Heart Failure: Assessment of reduction in mortality and morbidity (CHARM) programme consisted of three component trials. One, CHARM-Preserved, randomised 3023 patients with HF and a LVEF > 0.40 to placebo or candesartan (target dose 32 mg daily) 40 . The primary outcome of this study was the composite of cardiovascular death or heart-failure hospitalisation. There was only a non-significant trend towards a reduction in the primary endpoint with candesartan in this particular component trial (Fig. 1); a similar trend was observed for the pre-specified secondary endpoints (Fig. 2). Overall, however, there was no heterogeneity in the treatment effect of candesartan across all the CHARM trials or by ejection fraction (Figs. 3, 4). In other words, the CHARM Programme suggests that candesartan exerts a favourable effect across a broad spectrum of patients with HF, irrespective of LVEF or background therapy 41 . This is supported by the significant reduction in both the proportion of patients hospitalised with worsening heart failure (15% reduction, P = 0.017) and the total number of heart-failure hospitalisations (29% reduction, P = 0.014) in CHARM-Preserved (Fig. 5). Similarly, in CHARM-Overall, candesartan improved NYHA functional class, with no evidence of heterogeneity across the component trials. I-PRESERVE is another major morbidity/mortality trial comparing placebo to treatment with irbesartan in patients with HF-PSF. Patients must be 60 years or older and have a LVEF  0.45. In addition, patients in NYHA class II–IV CHF must have had a hospital admission for heart failure within the previous 6 months or, if NYHA class III or IV, have an abnormal chest radiograph (pulmonary oedema) or ECG (left-ventricular hypertrophy [LVH] or left bundle-branch block) or echocardiogram (LVH or enlarged left atrium). This trial is still in the recruitment phase.

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Digoxin

Treatment of heart failure with preserved systolic function: a review of the evidence

(a) Primary and secondary outcomes

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(b) Investigator-reported outcomes

Fig. 2. Effects of candesartan on (a) primary and secondary outcomes, and (b) investigator-reported outcomes in CHARMPreserved 40 .

Aldosterone blockers Excessive fibrosis may contribute to impaired relaxation and filling of the ventricles in HF-PSF, and aldosterone is thought to play an important role in this extracellular matrix change. The US National Institutes of Health are currently planning a trial with an aldosterone blocker in patients with HF-PSF.

Conclusions

Fig. 4. Cardiovascular deaths or hospitalizations in the CHARM Programme. Reproduced from Pfeffer et al. 41 with permission from Elsevier.

Fig. 5. Investigator-reported hospitalizations for CHF in CHARMPreserved 40 .

In summary, the development of treatments for HF-PSF has been neglected until recently. CHARM-Preserved is the only completed large randomised outcome trial, though the results of a number of ongoing trials are eagerly awaited. What can we conclude from the limited evidence currently available? There seems to be reasonable evidence that verapamil improves symptoms and exercise time in patients with HF-PSF. The safety and efficacy of this drug has been generally established in patients with hypertension and coronary heart disease 42 . Similarly, ARBs have established benefits in hypertension, myocardial infarction, HF-RSF and diabetic nephropathy. In CHARM, candesartan also substantially reduced the risk of heart-failure hospitalisation in patients with HF-PSF. In addition, candesartan improved NYHA class in the overall CHARM Programme without evidence of heterogeneity across the component trials or by LVEF.

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K. Hogg, J.J.V. McMurray