Ivabradine tolerability in heart failure

Sarah Birkhoelzer, Daniel Stevens, Donah Zachariah, Jackie Taylor, Nigel Rowell, Paul R Kalra

1Portsmouth Hospitals NHS Trust, UK

2Medical Affairs Department, Servier Laboratories UK

3Glasgow Royal Infirmary, UK

4South Tees Hospitals NHS Foundation Trust, UK

Keywords: Heart failure; Ivabradine; Quality of life; The elderly

The Systolic Heart failure treatment with the Ifinhibitor ivabradine Trial (SHIFT, n = 6505) evaluated patients with symptomatic chronic heart failure (CHF), in sinus rhythm with resting heart rate ≥ 70 beats/min and left ventricular ejection fraction (LVEF) ≤ 35%, average age 60 ± 11 years.[1]The addition of ivabradine, a selective inhibitor of the sinoatrial node, was associated with reduction in cardiovascular (CV) death or hospitalisation for worsening heart failure overall and in a subgroup of older patients (≥75 years, n = 722) compared with placebo.[2]Ivabradine is now incorporated into guidelines as an option if heart rate is not controlled with maximum tolerated dose of beta-blockers.[4]In elderly, frail patients with heart failure and multiple other comorbidities, there is increased focus on quality of life (QoL) in particularly the functional capacity. For many such patients improved QoL and maintenance of independence may be the priority.[5]

The oLder heart failure patients Initiated on iVabradinE in the UK: quaLIty of liFE (LIVE: LIFE) study is a multicentre, open-label, prospective, observational, study assessing health related QoL and functional endpoints in older patients following initiation of ivabradine in the context of usual clinical care.[6]The main results showed significant improvements in Health-Related Quality of Life (HRQoL)and functional status with ivabradine following 6 months of treatment (primary end point). Here we present the longterm (average of 15 months) use and tolerability of ivabradine from the LIVE: LIFE study.

LIVE: LIFE was carried out in 44 centres across England,Wales, Scotland and Northern Ireland. The aim was to assess HRQoL in older patients (age at least 70 years) followed-up for six months after clinically indicated initiation of ivabradine for treatment of CHF under the care of specialist cardiology, elderly care or community services. Patients consented for the research team to review medical records at V4, which was at least 12-months after their initial baseline visit (V1). This was not a formal face-to-face study visit.

Patients were recruited from December 2013 to March 2015. Study visits took place alongside usual clinical care at baseline (V1), 2 months (V2) and 6 months (V3). Data collected at V1-3 included patient demographics, clinical and HRQoL (MLWHFQ, SF-12), current medications, reasons for changes, hospitalisations and deaths. Assessment of tolerability of ivabradine was made where possible using a 5-point scale (very well, quite well, somewhat well, not well or not at all) by both patient and responsible healthcare professional. After follow-up of at least 12 months (data collection between March 2015 and September 2016), patients’long-term data (V4) were collected through review of medical notes and comprised hospitalisations, deaths, HF medications and healthcare professional’s tolerability assessment using the 5-point scale.

240 patients were recruited from 44 UK sites. 184 patients (76.3%) completed V3. Of these, by V4 15 patients died, and no data were available for a further six patients.As such data were available on 163 patients at both V3 and V4 and form the current study group.

The mean age of the patient cohort at V4 was 78 ± 6 years, 61% were male. Ischaemic heart disease was the commonest aetiology of heart failure (60%). Co-morbidities were common: 58% had history of hypertension, 33% diabetes and 44% asthma/COPD. The mean duration of follow-up since V1 was 456 ± 93 days, mean interval between V3 (last direct study contact with the patient) and V4 was 267 ± 97 days. Polypharmacy was common with an average of 9 daily prescribed medication at V3 and 11 at V4.

At V3, the majority (143, 88%) were taking ivabradine(doses: 2.5 mg b.d. n = 46; 5 mg b.d. n = 82; 7.5 mg b.d. n =15). Of 159 patients at V4 with data available regarding ivabradine use at that point 75% (119/159) remained on ivabradine (doses: 2.5 mg b.d. n = 29; 5 mg b.d. n = 76; 7.5 mg b.d. n = 14).

Recommendation to stop Ivabradine was most commonly made by the heart failure team (n = 18), primary care(n = 5) and non-heart failure secondary care (n = 3). Reasons given for discontinuing ivabradine included controlled heart rate, low blood pressure, orthostatic hypotension, rash,sleepiness, atrial fibrillation (n = 4), renal injury and shortness of breath. In 14 cases, the reason for stopping ivabradine was not documented. At V4 healthcare professionals felt able to comment on tolerability of ivabradine for 113 patients: “somewhat well or better” was seen in 105.

At V4, 58% were receiving a beta-blocker (61% at V3),69% an angiotensin-converting-enzyme inhibitor/angiotensin receptor blocker (87% at V3), and 40% a mineralocorticoid receptor antagonist (39% at V3). Between V3 and V4 24% (39/163) patients had been hospitalized, in all cases due to complication of heart failure.

LIVE: LIFE is a multi-centre, observational cohort study across 44 sites serving a wide geographical area within the UK. Due to the nature of the study, the cohort is more representative of that seen in standard clinical practice than many interventional studies; the mean ages of patients in land mark heart failure trials are typically between 60 and 69 years.[5]In contrast to SHIFT,[1]which consisted of patients with an average age of 60 years, LIVE: LIFE recruited patients with heart failure aged ≥ 70 years as this is often the lower age limit for admission to specialist services for older people. This study consists of patients with a mean age of 78 years with multiple comorbidities and treated with polypharmacy, in keeping with day to day practice. The data collected allows analysis of the current practice across 44 sites and is likely to be representative of the UK. The fact that recruitment took over 12 months is suggestive of an appropriate indication to use ivabradine after attempts at up-titration of beta-blockade. This is in keeping with the recommendations within the National Institute for Health and Care Excellence guidelines TA267 (i.e., symptomatic CHF with systolic dysfunction, sinus rhythm with resting heart rate ≥ 75 beats/min, combination with standard therapy including beta blockers or when beta blockers are contraindicated or not tolerated).[4]

Patients within this cohort do seem to present a therapeutic challenge, receiving relatively low rates of disease modifying drugs: at V4 less than 3/5 of patients were taking beta blockers, around 2/3 were on an angiotensin-converting-enzyme inhibitor/angiotensin receptor blocker and 2/5 on a mineralocorticoid receptor antagonist. Of 159 patients at V4, with data available regarding ivabradine use,75% remained on ivabradine. However, 40 had stopped ivabradine before V4. The majority of reason to discontinue ivabradine was due to haemodynamic concern.

These data provide clinicians with further evidence on ivabradine in typical older heart failure patients which can help to inform patient-centered discussion on impact on HRQoL and drug tolerability, and builds on the original SHIFT study results.[6]

There are limitations to an open-label, observational cohort study in particularly when assessing HRQoL. As ivabradine is recommended by international guidelines,[4]a placebo-controlled trial was deemed unethical. An effect on adherence to ivabradine due to participating in research can’t be excluded, although the fact that final contact (V4)was on average almost nine months after the last face-toface contact with the research team would be against this being a major influence.

In the majority of elderly patients with heart failure ivabradine is well tolerated in the longer-term (around 15 months follow up), despite the presence of multiple co-morbidities and polypharmacy. These data reflect real-world practice in the UK—the final data were collected almost nine months after the last study contact with the patient.Further evaluation is required to elucidate reasons for stopping ivabradine and neurohormonal antagonists.

Acknowledgements

This research was funded and supported by Servier Laboratories (UK) ltd. Dr. Birkhoelzer and Dr. Zachariah report no conflicts of interest; Stevens D reports personal fees from Servier during the conduct of the study and outside the submitted work; Dr. Rowell reports personal fees from Servier, during the conduct of the study; Dr. Taylor reports grants and personal fees from Servier, during the conduct of the study; Dr. Kalra reports personal fees from Servier, during the conduct of the study; personal fees and other from Servier outside the submitted work.