This is a fairly critical study. It appears to have uncovered a potential direct link between the addition of a second Bronchodialator and Heart Failure risk. It appears this jhas shown up after 1 year follow-ups pon patients.
While this study indicates a risk it does not provide any hard conclusions (not surprising they rarely do). However, it maybe something to discuss with ones Respiratory specialist. If you are going to take a printout I would recommend you print the attached PDF file
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COPD and bronchodilators: should the heart pay the bill for the lung?
Nera Agabiti and Giuseppe Maria Corbo
The pharmacological treatment of patients with coexisting cardiovascular disease (CVD) and chronic
obstructive pulmonary disease (COPD) is challenging, because some drugs for COPD patients should be
used with caution in patients with CVD, and vice versa. The crucial question on cardiovascular safety of
long-acting bronchodilators, i.e.long-acting β2-agonists (LABAs) and long-acting anti-muscarinic agents
(LAMAs, principally tiotropium), has no definitive answer. Because of different mechanisms of action, the
combination of these drugs is expected to be more effective than the individual components in the
maintenance treatment of COPD. Evidence available from randomised controlled trails and
observational studies on increased risk of cardiovascular adverse events is large but difficult to summarise
because of complex methodology, different comparison groups and potential bias in each study.
Results are controversial and inconclusive. The risks of combining LABAs and tiotropium for the
treatment of COPD are still unclear. Whether COPD patients treated with long-acting bronchodilators
have increased risk of heart failure, or patients with both COPD and heart failure have higher risk of
adverse events, remain open questions.
What the study addsIn this issue of the
European Respiratory Journal, the study presented by SUISSA et al. interestingly
contributes to the ongoing debate. The focus is on the concurrent use of long-acting bronchodilators.
A large COPD patient cohort was selected from the UK Clinical Practice Research Datalink for 2002–2012
and followed up over 1 year. Compared with monotherapy, adding a second long-acting bronchodilator
(either a LABA or tiotropium) did not increase the risk of myocardial infarction, stroke or arrhythmia.
However, a statistically significant
% increase in the risk of heart failure was found with the addition of
a second long-acting bronchodilator rather than monotherapy; the increase was higher (23%) when
patients with previous diagnosis of heart failure (about 3% of the whole study population) were excluded.
Large numbers from real-world settings, sophisticated analytical approaches and sensitivity analyses led to
robust results, considering the known limits of observational studies on the comparative effectiveness and
safety of drugs. The fact that the use of two long-acting bronchodilators was found to be safe, in terms of
major cardiovascular events, is reassuring and supports the guidelines/recommendations regarding the use
of fixed-dose combination bronchodilators. However, the effect on heart failure is relevant and deserves
some additional consideration.
Relationship between COPD and CVDHeart–lung interactions are complex, particularly in the context of heart failure. CVD is undoubtedly the
most significant non-respiratory contributor to both morbidity and mortality in COPD.
The prevalence of
CVD in patients with COPD was found to range from 7.1% to 31.3% for heart failure, from 4.7% to 60%for
ischaemic heart disease, from 0.3% to 29% for arrhythmia and from 6.9% to 9.9% for stroke. The
strong overlap between the two conditions is due to shared similar risk factors, such as ageing, smoking,
exposure to environmental pollution, metabolic disorders and altered inflammatory response. On
the one hand, the increased risk of CVD persists after adjustment for common risk factors, suggesting that
COPD plays a role in the development of CVD. On the other hand, COPD patients with a more severe
reduction of forced expiratory volume in 1 s have a greater risk of occurrence of heart failure, atrial
fibrillation and myocardial infarction.
COPD is frequent and often undiagnosed among patients with
heart failure (with rates from 13% to 38%) and is associated with higher mortality. Over the last
few years, researchers and clinicians have focused on the autonomic nervous system, which is impaired in
both COPD and CVD. Heart rate variability is frequently used as a measure of autonomic control. It
has been found that COPD patients have a reduced heart rate variability and that autonomic control
during exercise is altered. A reduction in heart rate variability reflects a sympathetic activation; this is
a prognostic factor in ischaemic heart disease, heart failure, hypertension and stroke. Clinical
trials on the safety of these drugs on cardiovascular autonomic control have been performed, but
the absence of adverse effects could not be excluded, because of the selection of samples and the short
duration of the studies. The complex relationship between CVD and COPD is summarised in figure 1.
Relationship between COPD and heart failure
Heart failure is a complex syndrome owing to the inability of the heart to pump sufficient blood to meet
the needs of the body’s tissues. It represents the end stage of cardiac disease, mostly following coronary
disease or hypertension. Two distinct clinical syndromes have been identified: heart failure with reduced
ejection fraction (HFrEF), i.e.EF <40%, which is characterised by abnormalities in left ventricular systolic
function, progressive chamber dilation and eccentric remodelling, and heart failure with preserved ejection
fraction (HFpEF), i.e.EF⩾50%, which presents normal or near normal systolic function and evidence
of diastolic dysfunction with concentric remodelling or hypertrophy. Heart failure with mid-range EF
(i.e.EF range 40%–49%) has recently been labelled. About half of patients with heart failure have a
normal ejection fraction.
( diagram located here in attached PDF )
FIGURE 1.The complex interaction between chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD).
Although patients with heart failure present similar clinical signs and symptoms, it is important to
distinguish the various forms of heart failure because they differ in pathophysiology, structural changes in
the cardiac muscle, neuro-humoral and inflammatory molecular mechanisms, epidemiology, potential
susceptibility to environmental triggers and response to treatment. Some biomarkers have been linked
to the heart failure subtypes. For example, plasma B-natriuretic peptide concentration in patients with
HFpEF was lower than in patients with HFrEF, and highly sensitive troponin T was significantly associated
with development of HFrEF; in contrast, growth factor GDF, cystatin C and urinary albumin excretion
were significantly associated with the development of HFpEF. Opportunities and challenges of old
and new pharmacological treatments of heart failure patients have been updated in the clinical guidelines. However, the role of both beta-blockers and ACE/ARB (angiotensin-converting enzyme/angiotensin
receptor blocker) in HFpEF is not well established and there is no evidence-based optimal therapeutic
protocol for HFpEF.
In this respect, the finding from the study by SUISSA et al., that concomitant use of long-acting
bronchodilators influences the incidence of new heart failure (hazard ratio 1.21 among those with no heart
failure diagnosis before cohort entry), suggests that these drugs play a role in the development of heart
failure in COPD patients in a 1-year follow-up period. Accurate identification of COPD subgroups that are
potentially more vulnerable to cardiac drug toxicity is crucial. Measuring coexisting cardiac diseases,
subtypes and severity of heart failure, conditions/comorbidities associated with poor prognosis such as
peripheral artery disease or diabetes, and severity of lung function impairment is challenging, but cannot
be fully achieved in large observational studies based on healthcare electronic databases. Because clinical
presentation is fundamental to the diagnosis of heart failure, and heart failure and COPD share both risk
factors and clinical presentation, making the correct diagnosis may be difficult. Acute respiratory
symptoms may have mixed pulmonary and cardiac origin . Echocardiography is the cornerstone for
the diagnosis of heart failure, but in patients with pulmonary emphysema, air trapping may alter
echocardiographic acoustic windows, leading to poor image quality in many COPD patients].
Moreover, N-terminal pro-brain natriuretic peptide may improve the diagnostic accuracy of heart failure in
stable COPD.
Rigorous measurement of drug use that is potentially dangerous for the heart is another crucial point in
pharmacological safety research, with a particular focus on potential interaction between drugs and a
consideration of patients’ adherence to medical prescription and how this changes over time. The
increased risk of heart failure resulting from the addition of a LABA rather than tiotropium (hazard ratio 1.28
versus 1.11) compared with the risk of monotherapy is another interesting finding from the work of
SUISSA et al., and the hypothesis of a trigger action of LABAs in precipitating heart failure cannot be
ruled out. Longer follow-up studies could elucidate this aspect. Mechanisms for decompensated heart
failure are complex and not fully understood. Multiple risk factors have been proposed and include
ischaemia, arrhythmia, respiratory infections, COPD exacerbations and air pollution.
Conclusions
SUISSA et al. have added important data to the ongoing debate on the cardiac safety of long-acting
bronchodilators. Given the rapid development of new molecules to treat COPD, there is a need for timely
information from high-quality studies on both the effectiveness and safety of single drugs alone, and their
combination. Efforts should be made to interpret and summarise findings originating from different
research approaches, i.e.randomised controlled trials and observational studies, to guide decision-making
from both clinical and drug-regulatory perspectives. COPD patients with concomitant CVD
diseases represent a big everyday challenge for clinicians. Cardiologists and pulmonologists should work
together in the context of an integrated care approach to optimise the management of the complex
multimorbid COPD population.
erj.ersjournals.com/content/erj/49/5/1700370.full.pdf
% increase in the risk of heart failure was found with the addition of