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Role of Statins in Management and Outcomes of Heart Failure
In order to distinguish essays and pre-prints from academic theses, we have a separate category. These are often much longer text based documents than a paper.
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.