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Role of Statins in Management and Outcomes of Heart Failure
thesis
posted on 2017-02-07, 22:58authored byKwadwo Osei Bonsu
Heart failure
places a heavy burden not only on patients and their families but the entire
society, through enormous use of health care resources. Heart failure is a
clinical syndrome which has fast become a public health problem worldwide and
thus requires a global response. Studies have shown that, aetiology,
progression, form, clinical characteristics, prognosis and response to
pharmacological treatment of heart failure vary across different races.
However, data on heart failure had mostly come from Caucasian populations with
very little from populations in the developing world. Despite significant
strides made in recent decades in treatment of patients with heart failure,
morbidity and mortality is still high and requires further and urgent
strategies to avert or reduce adverse outcomes. Statins are among the novel but
affordable pharmacological treatments that have been investigated in heart
failure in recent times.
Statin treatment is established for prevention of
cardiovascular events. However, role of statins in heart failure is unclear and
remains a subject of intense debate. Evidence from observational studies,
retrospective data, post hoc analyses of data from large statin trials in
various cardiovascular conditions as well as small scale randomised trials,
suggest outcome benefits for heart failure. However, two large randomised
trials–CORONA and GISSI-HF–which evaluated only one type of statin at a low
dose appear to suggest statins do not improve outcomes of patients with HF. In
addition to lowering cholesterol, statins are believed to have many pleotropic
effects which could possibly influence the pathophysiology to enhance heart
failure survival. Evidence from recent studies appears to support the use of
statins and suggest that lipophilic statins have better outcomes compared with
hydrophilic statins in heart failure.
This thesis examines the role of statins in outcomes of heart
failure in two phases. The first phase evaluates statin treatment and outcomes
of heart failure using existing clinical trial data through a systematic review
and meta-analyses. With the existing clinical trial data, we compared outcomes
with lipophilic and hydrophilic statin treatment using indirect adjusted
comparison meta-analyses. The second phase examines the treatment effect of
statins and long-term clinical outcomes of heart failure among African
population using a retrospective longitudinal cohort study conducted in a
tertiary healthcare centre in Ghana. The thesis is a compilation of seven
papers (five published, and two under review), segmented into two phases, with
a brief narrative drawing the themes together.
The topic is introduced with an overview which briefly
narrates the disease burden and recent advances in management of heart failure.
Following this overview is an extensive review paper on the role statins in
heart failure. This review raises important clinical questions about the lack
of clarity surrounding the effect of statins in heart failure. These doubts
originate from the lack of outcome benefits of two large trials in heart failure.
This review discusses the role of statins in the pathophysiology of heart
failure, current evidence for statin use in heart failure, as well as
identifying important gaps for further research. Our review affirm earlier
claims that lipophilic statins have better outcomes compared with hydrophilic
statins and suggests the need for head to head comparison trial in heart
failure. It further suggested that, in the absence of any trials directly
comparing the efficacy of lipophilic and hydrophilic statins on outcomes in HF,
one approach is to conduct an adjusted indirect comparison of the existing
trial data with a common control. Use of indirect comparison meta-analytic
approaches allows for adjusted head-to-head comparisons when treatments share a
common comparator, in this case placebo or no statin treatment arms of trials.
The gaps identified coupled with the arguments advanced in the review granted
the basis for the conduct of indirect comparison meta-analyses of lipophilic
and hydrophilic statins on outcomes in HF to provide clinicians and researchers
with important information on which clinical decisions can be made. In
addition, the review identified that evidence for statin use in HF had come
from mostly Caucasian populations. Indeed, race and ethnic differences play
important roles in clinical characteristics, treatment and prognosis of heart
failure. And this provided the rationale for the retrospective longitudinal
cohort study in an African population with heart failure in the second phase of
the thesis.
Having identified the gaps in evidence for statin use in
heart failure and providing the rationale for comparison of the statin types on
outcomes of heart failure, we drew a protocol for the systematic review and
comparison meta-analyses. The protocol shed more light on the rationale,
detailed methodology and provided a guide for the meta-analyses. Subsequent to
the protocol is a paper reporting the results of the comparison of lipophilic
and hydrophilic statin treatment on surrogate outcomes (indices of cardiac
function and inflammation) of more than 6200 heart failure patients enrolled in
19 randomized controlled trials (RCTs). The meta-analyses demonstrated that
lipophilic statins are associated with greater treatment effects on cardiac function
and inflammation compared with hydrophilic statin in heart failure. The second
paper from the meta-analyses compares the efficacy of lipophilic and
hydrophilic statins in clinical outcomes (mortality and hospitalization) in
heart failure. Lipophilic statin treatment demonstrated significant reduction
in mortality and hospitalization outcomes compared with hydrophilic
rosuvastatin in about 11000 patients with heart failure enrolled in 13 RCTs.
The observed differences between the two statin types were meaningful, robust,
and highly statistically significant and could be explained by known
differences in pharmacologic properties of lipophilic and hydrophilic statins.
It is thus, reasonable to conclude that, differences in treatment effect
between lipophilic and hydrophilic statins on indices of cardiac function and
inflammation could have accounted for treatment benefits in clinical outcomes
observed with lipophilic statin use in heart failure. Until data from
adequately powered head to head clinical trials of the statin types are
available, these meta-analyses provides preliminary evidence that lipophilic
statins offer better clinical and surrogate outcomes in heart failure.
In addition to the doubt raised in the generalizability of
the two large statin trials, because of the focus on hydrophilic statins, the
patient groups were overwhelmingly of Caucasian (White) background. Race and
ethnic differences play important roles in patient characteristics, treatment
and prognoses of heart failure. While this phase primarily aimed to test the
effect of statins on long term outcomes, a secondary aim examined the long-term
survival and independent predictors of mortality of heart failure in black
Africans. Whereas the clinical characteristics, progression, treatment and
outcomes may be well studied in other populations, available but scanty data
suggest poor prognosis of heart failure among Sub-Saharan Africans and
predictors of long-term mortality outcomes have hitherto not been studied. Thus
the first paper of the second phase of the thesis describes the clinical
characteristics, long-term survival and prognostic factors that predict
mortality of Africans with heart failure. In addition to the survival and
predictors of mortality in the overall study cohort, this paper further
examines the factors that predict outcomes of cohorts with reduced and
preserved ejection fraction in predominantly black African population. The
understanding of the basic survival and knowledge of the determinants of worse
outcomes provided the basis for making better contextual interpretations to
estimates of statin treatment effects obtained from the analyses of data from
the cohort.
The final paper shows that, in our cohort of black Africans
with heart failure, statin treatment was associated with significant reduction
in mortality for all-cause, cardiovascular and worsening heart failure
mortality. In the absence of RCTs, appropriate adjustment for time-varying
confounding by indication may provide the best evidence to estimate treatment
effects with non-randomized studies. These findings were consistent across both
inverse probability treatment (IPT) weighted analysis and the overall analysis
adjusting for clinically relevant covariates. Importantly, lipophilic statin
use in patients with heart failure was associated with reduced mortality
outcomes (compared with no statin treatment) but this effect was not observed
using hydrophilic statins in patients with heart failure. This finding suggests
that additional RCTs evaluating statins other than hydrophilic rosuvastatin
with longer follow-up will be necessary. Further, it would be remarkable to
compare lipophilic and hydrophilic statin treatment on clinical outcomes in a
head to head trial of patients with heart failure.
History
Principal supervisor
Amudha Kadirvelu
Additional supervisor 1
Daniel Reidpath
Year of Award
2017
Department, School or Centre
Jeffrey Cheah School of Medicine and Health Sciences (Monash University Malaysia)