HF medication prescription and overall survival
Potential predictors of mortality are presented in Table 4. Older age at device implant, renal dysfunction, CRTD implant (rather than ICD), and VA episodes during F/U were associated with increased overall mortality. Analysis of HF medications showed that combined treatment with all 3 HF medication groups (p=0.0047) and treatment with AngA per se (p 0.028), regardless of dose, were significantly associated with reduced mortality (Table 4).
In a univariate analysis the following parameters were significantly associated with overall mortality: age (HR 1.06; 95% CI1.04-1.09; p=0.0001), renal dysfunction (HR 1.63; 95% CI1.03-2.56; p=0.037), CRTD (versus ICD) (HR 1.67; 95% CI1.03-2.71; p=0.036), VA during F/U (HR 2.76; 95% CI 1.474-4.967, p=0.001) and AngA treatment ( HR 0.55; 95% CI 0.31-0.97; p=0.039).
In Cox multivariable survival analysis including patients’ age, gender, renal function, HF medication treatment, and VA occurrence during F/U, AngA treatment (but not BB or MRA) was significantly associated with reduced mortality (HR 0.515; 95% CI 0.285-0.929; p=0.028); while age (HR 1.06; 95% CI 1.038-1.093; p=0.0001); renal disease (HR 1.728; 95% CI 1.070-2.792; p=0.025); and VA during F/U (HR 2.672; 95% CI 1.429-4.999; p=0.002) were significantly associated with increased mortality (Table 5).
Kaplan-Myer overall survival analysis according to HF medication groups showed reduced mortality among patients with AngA (p=0.036) without significant impact of BB or MRA (Figure 3). Interestingly, Kaplan-Myer overall survival curves for the combination of all 3 HF medication groups diverged for improvement with combined treatment after 4 years (curve not shown). Kaplan-Myer overall survival curves by incident VA (as a competing event) revealed increased mortality in patients with VA (Figure 4).
Discussion
This study, including 186 HF patients implanted with a primary prevention ICD or CRTD and meticulously followed in the device clinic, evaluated the impact of guideline-based HF medications on incident VA and total mortality. During the median F/U period of 3.8 years, 28% of the patients had VA and 41.4% died. On the whole, although most of the patients were prescribed with the appropriate HF medications (> 80% for BB and AngA and 60% for MRA), the doses were low. The median dose of HF medications in the current study was 25% of target dose for all 3 medication groups with less than 20% of patients treated by >50% target dose. We found that treatment with lower doses of BBs and increased heart rates were both significantly and independently associated with increased VA, while DM was associated with reduced VA incidence. We also found that treatment with AngA was significantly associated with reduced overall mortality, while VA and renal dysfunction were associated with increased mortality.
The incidence of VA in the current study is comparable to previously published studies. In the SCD-HeFT primary prevention trial which had a similar F/U period, the incidence of appropriate ICD shocks was 21.5% (26). The estimated annual incidence of VA in our study of 7.4% is similar to the 7.2% annual appropriate shock incidence in the DEFINITE primary prevention trial (27). Notably, the patients’ devices in the current study were routinely programmed via prolonged VA detection periods to enable spontaneous termination of short VAs, as well as device intervention for relatively fast VAs. Thus, only long and fast VAs were included in the current study. Importantly, these clinically relevant VAs do not equal sudden cardiac death, as they might still end spontaneously (28-30). Nevertheless, these VAs do have a significant impact on overall mortality, as was shown in the current study and as supported by several prior studies establishing the benefit of ICD implant (26,27,31-34).
In the current study the dosage of BB, rather than their mere use, was associated with VA reduction. The importance of aiming for target doses was previously studied, revealing increased deaths and/or HF hospitalizations among HF patient treated by < 50% target dose of BB and ACE-I (7,20,24). The importance of HF medication dosage was further emphasized in the DANISH trial where optimal medical therapy, with medication prevalence of >90% for BB and AA and 60% for MRA (similar to current study) and doses that were increased to target doses whenever possible, were suggested to obviate the survival benefit of an ICD (16). Lastly, a recent meta-analysis including six pivotal randomized trials of DCM patients, showed a significant survival benefit of ICD plus medical therapy compared with medical therapy alone, but this survival benefit was lost in trials where >50% of patients were treated via combination of BB, AngA, and MRA with doses reaching guideline target doses (14). On the whole, our study suggests that HF medication dosage in general and BB dose specifically, is important for reducing VA in advanced HF patients implanted with an ICD or CRTD.
Potential mechanisms for antiarrhythmic effects of BB include their anti-sympathetic effect resulting in reduced heart rates and increased heart rate variability, direct anti-arrhythmic effect, reducing intra-cellular Ca within cardiac cells, improving cardiac function, reducing cardiac ischemia and more (35,36). In the current study, reduced BB doses were associated with increased VA even when adjusting for heart rate. Therefore, BBs may have an anti-arrhythmic effect beyond decreasing heart rate per se. This result is in line with previous trials (37-39), which show that although increased heart rates are associated with worst outcomes in HF patients, increasing BB dose regardless of baseline heart rates is associated with an improved combined outcome of all-cause mortality and HF hospitalizations. Accordingly, we as others (37-39), suggest that BB dose up-titration regardless of baseline heart rate should be considered for VA prevention (as long as symptomatic or excessive bradycardia is absent).
Low dosing of all HF recommended medications was one of main findings in the current study. Low dosing was noticed in multiple HF studies and registries (17-20,24), acknowledging this is a universal problem. For example, in the CHAMP-HF registry including 3500 HF patients with reduced EF from 150 medical centers, less than 25% of patients received target dose of any HF medication and only 1% received target dose of all 3 HF family medications (17,18). Similarly, only a minority of patients in the Asian (19) and pan-European (24) registries received target doses of any HF medication. Low dose HF medications could result from inadequate medical surveillance, non-referral to specialized HF clinic, or otherwise impacted by various ’obstacles’ such as low blood pressure or heart rate, co morbidities, and medication-related side effects preventing one from achieving target doses. In the current study, patients with and without VA had similar co morbidities, with HTN in most patients and heart rates between 70-80 bpm in both groups. Hence, we suggest that the lower BB dosage among patients with VA is not related to sicker patients who cannot tolerate increased BB doses but rather suboptimal medical surveillance. This corroborates with the limited number of study patients who were followed in the HF clinic (enjoying better adherence to treatment). Indeed, in reality many ICD/CRTD candidates are referred to an EP clinic by their general cardiologists or GPs for device implantation without HF consultation and with inadequate HF medical treatment. Thus, we suggest that all HF patients and especially those referred to device implant undergo HF specialist consultation, aiming to achieve HF medication target doses. Importantly, this approach is strongly supported by both EP and HF guidelines advocating ICD or CRTD implant only after confirmation of optimal HF medical treatment (21-23).
Strengths and Limitations
Our study has several limitations including: a) its retrospective nature; b) single center data; c) the overall low doses of guideline-based medications, resulting in possible underestimation of medication effect; d) discharge prescriptions may not equal true medical treatment over time, although most patients remain treated with their discharge recommendations; e) most study patients were included prior to 2016 and thus were not treated with angiotensin receptor/neprilysin inhibitors (ARNI). Thus, our study did not evaluate impact of ARNI, which is a pivot HF medication in recent years; f) data on cause of death is missing. The study also has several strengths including the meticulous retrieval of VA events and the in-depth manual evaluation of discharge medication dose analyzed as the proportion of guideline recommendations.
Conclusion:
In this single center retrospective cohort of CHF patients implanted with an ICD/CRTD for primary prevention, we found a relatively high prevalence of HF guideline-recommended medication treatment albeit with low doses. Reduced BB doses were associated with an increased VAs which in turn are associated with increased mortality, while treatment with AngA was associated with reduced overall mortality. Specialized HF consultation is therefore advocated for these patients referred for primary prevention ICD/CRTD to improve their medical treatment and outcomes.
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Table 1 - Patient characteristics and comparison of patients with and without VA