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Re: Targeting NOS as a therapeutic approach for heart failure

Bonsu KO, Kadirvelu A, Reidpath DD

Pharmacol Ther, 2014 Sep;143(3):350.
PMID: 24769330 DOI: 10.1016/j.pharmthera.2014.04.003
Fulltext Statins in heart failure: do we need another trial?

Bonsu KO, Kadirvelu A, Reidpath DD

Vasc Health Risk Manag, 2013;9:303-19.
PMID: 23807852 DOI: 10.2147/VHRM.S44499

Statins lower serum cholesterol and are employed for primary and secondary prevention of cardiovascular events. Clinical evidence from observational studies, retrospective data, and post hoc analyses of data from large statin trials in various cardiovascular conditions, as well as small scale randomized trials, suggest survival and other outcome benefits for heart failure. Two recent large randomized controlled trials, however, appear to suggest statins do not have beneficial effects in heart failure. In addition to lowering cholesterol, statins are believed to have many pleotropic effects which could possibly influence the pathophysiology of heart failure. Following the two large trials, evidence from recent studies appears to support the use of statins in heart failure. This review discusses the role of statins in the pathophysiology of heart failure, current evidence for statin use in heart failure, and suggests directions for future research.
Fulltext Lipophilic versus hydrophilic statin therapy for heart failure: a protocol for an adjusted indirect comparison meta-analysis

Bonsu KO, Kadirvelu A, Reidpath DD

Syst Rev, 2013;2:22.
PMID: 23618535 DOI: 10.1186/2046-4053-2-22

Statins are known to reduce cardiovascular morbidity and mortality in primary and secondary prevention studies. Subsequently, a number of nonrandomised studies have shown statins improve clinical outcomes in patients with heart failure (HF). Small randomised controlled trials (RCT) also show improved cardiac function, reduced inflammation and mortality with statins in HF. However, the findings of two large RCTs do not support the evidence provided by previous studies and suggest statins lack beneficial effects in HF. Two meta-analyses have shown statins do not improve survival, whereas two others showed improved cardiac function and reduced inflammation in HF. It appears lipophilic statins produce better survival and other outcome benefits compared to hydrophilic statins. But the two types have not been compared in direct comparison trials in HF.
Lipophilic Statin Versus Rosuvastatin (Hydrophilic) Treatment for Heart Failure: a Meta-Analysis and Adjusted Indirect Comparison of Randomised Trials

Bonsu KO, Reidpath DD, Kadirvelu A

Cardiovasc Drugs Ther, 2016 Apr;30(2):177-88.
PMID: 26780905 DOI: 10.1007/s10557-015-6636-z

OBJECTIVES: This study aims to compare lipophilic and hydrophilic statin therapy on clinical outcomes of heart failure (HF) using a systematic review and an adjusted indirect comparison meta-analysis. Outcomes were all-cause mortality, cardiovascular mortality, cardiovascular hospitalization and hospitalization for worsening HF.
METHODS: We conducted a search of PubMed, EMBASE and Cochrane databases until 31st December 2014 for randomized control trials (RCTs) in HF evaluating statins versus placebo. Identified RCTs and their respective abstracted information were grouped according to statin type evaluated and analyzed separately. Outcomes were initially pooled with the Peto's one-step method, producing odd ratios (OR) and 95 % confidence intervals (CI) for each statin type. Using these pooled estimates, we performed adjusted indirect comparisons of lipophilic versus hydrophilic statin for each outcome.
RESULTS: Thirteen studies involving 10,966 patients were identified and analyzed. Lipophilic statins were superior to hydrophilic rosuvastatin regarding all-cause mortality (OR 0 · 50; 95 % CI, 0 · 11-0 · 89; p = 0 · 01), cardiovascular mortality (OR 0 · 61; 0 · 25-0 · 97; p = 0 · 009), and hospitalization for worsening HF (OR 0 · 52; 0 · 21-0 · 83; p = 0 · 0005). However, both statins were comparable with regards to cardiovascular hospitalization [OR 0 · 80 (0 · 31, 1 · 28); p = 0 · 36].
CONCLUSIONS: Lipophilic statin treatment shows significant decreases in all-cause mortality, cardiovascular mortality and hospitalization for worsening HF compared with rosuvastatin treatment. This meta-analysis provides preliminary evidence that lipophilic statins offer better clinical outcomes in HF till data from head to head comparisons are available.
Effects of Statin Treatment on Inflammation and Cardiac Function in Heart Failure: An Adjusted Indirect Comparison Meta-Analysis of Randomized Trials

Bonsu KO, Reidpath DD, Kadirvelu A

Cardiovasc Ther, 2015 Dec;33(6):338-46.
PMID: 26280110 DOI: 10.1111/1755-5922.12150

Statins are known to prevent heart failure (HF). However, it is unclear whether statins as class or type (lipophilic or hydrophilic) improve outcomes of established HF.
Pharmacological treatments for heart failure with preserved ejection fraction-a systematic review and indirect comparison

Bonsu KO, Arunmanakul P, Chaiyakunapruk N

Heart Fail Rev, 2018 03;23(2):147-156.
PMID: 29411216 DOI: 10.1007/s10741-018-9679-y

Pharmacological interventions for heart failure with preserved ejection fraction (HFpEF) have failed to reduce mortality and hospitalization. Evidence for mineralocorticoid antagonists (MRAs), β-adrenoceptor blockers (β-blockers), and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs)-to reduce clinical outcomes in HFpEF remains unclear. We conducted a systematic search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Clinical Trials.gov for randomized controlled trials (RCTs) assessing pharmacological treatments in HFpEF diagnosed according the recommendations of the European Society of Cardiology (ESC) 2016 guidelines from inception to August, 2017. The study outcomes were mortality, hospitalization, changes in indexes of cardiac structure and function, biomarkers, and indexes of functional capacity-quality of life (QoL) assessment and 6-min walk distance test (6-MWD). The random-effects models were used to estimate pooled relative risks (RRs) for the binary outcomes and standardized mean differences for continuous outcomes, with 95% CI. A network meta-analysis using a random-effects model was employed to estimate the comparative efficacy of treatments. We included data from 15 RCTs comprising 5930 patients. There was no significant effect seen with all treatments compared with placebo and comparative efficacy of any two treatments on all outcomes assessed. However, mineralocorticoid antagonist spironolactone demonstrated a trend towards reducing mortality compared with placebo (RR 0.92; 95% CI 0.79-1.08), sildenafil (0.14; 0.01-2.78), perindopril (0.87; 0.59-1.28), and eplerenone (0.91; 0.25-3.33). Similar trends in treatment effect were observed with spironolactone on surrogate outcomes while eplerenone demonstrated a trend of superior effect in reduction of hospitalizations compared with all other drug treatment. No drug treatment demonstrated statistically significant improvement in clinical and surrogate outcomes in HFpEF diagnosed according to the ESC 2016 guideline. Spironolactone and eplerenone showed clinically relevant reduction in mortality and hospitalization respectively compared with other drug treatments. Further trials with MRAs are warranted to confirm treatment effects in HFpEF.
Fulltext Effectiveness and safety of statins on outcomes in patients with HIV infection: a systematic review and meta-analysis

Vigny NN, Bonsu KO, Kadirvelu A

Sci Rep, 2022 Oct 27;12(1):18121.
PMID: 36302940 DOI: 10.1038/s41598-022-23102-2

Statins are hypolipidaemic in human immunodeficiency virus (HIV) positive individuals. However, their effect on all-cause mortality and rate of discontinuation is unclear. We conducted a systematic review to evaluate the impact of statins on all-cause mortality, discontinuation rates, and risk of adverse effects among HIV patients on highly active antiretroviral therapy (HAART). We searched four electronic databases from inception until October 2021 for trials and cohort studies evaluating the effects of statin treatment versus placebo in HIV patients. Forty-seven studies involving 91,594 patients were included. Statins were associated with significantly lower risk of discontinuation (RR, 0.701; 95% CI 0.508-0.967; p = 0.031). The risk of all-cause mortality (RR, 0.994; 95% CI 0.561-1.588; p = 0.827), any adverse effects (RR, 0.780; 95% CI 0.564-1.077; p = 0.131) and, diabetes mellitus (RR, 0.272; 95% CI 0.031-2.393; p = 0.241) with statin treatment were lower but not statistically significant compared to placebo/control. Statin treatment was associated with a trend of higher but statistically insignificant risk of myalgia (RR, 1.341; 95% CI 0.770-2.333; p = 0.299), elevated creatine kinase (RR, 1.101; 95% CI 0.457-2.651; p = 0.830) and liver enzyme activities (RR, 1.709; 95% CI 0.605-4.831; p = 0.312). Clinicians should consider the nocebo effect in the effective management of PLWH on statins, who present with common adverse effects such as myalgia and, elevated levels of creatine kinase and liver enzymes.
Fulltext Statin Treatment and Clinical Outcomes of Heart Failure Among Africans: An Inverse Probability Treatment Weighted Analysis

Bonsu KO, Owusu IK, Buabeng KO, Reidpath DD, Kadirvelu A

J Am Heart Assoc, 2017 Apr 01;6(4).
PMID: 28365564 DOI: 10.1161/JAHA.116.004706

BACKGROUND: Randomized control trials of statins have not demonstrated significant benefits in outcomes of heart failure (HF). However, randomized control trials may not always be generalizable. The aim was to determine whether statin and statin type-lipophilic or -hydrophilic improve long-term outcomes in Africans with HF.
METHODS AND RESULTS: This was a retrospective longitudinal study of HF patients aged ≥18 years hospitalized at a tertiary healthcare center between January 1, 2009 and December 31, 2013 in Ghana. Patients were eligible if they were discharged from first admission for HF (index admission) and followed up to time of all-cause, cardiovascular, and HF mortality or end of study. Multivariable time-dependent Cox model and inverse-probability-of-treatment weighting of marginal structural model were used to estimate associations between statin treatment and outcomes. Adjusted hazard ratios were also estimated for lipophilic and hydrophilic statin compared with no statin use. The study included 1488 patients (mean age 60.3±14.2 years) with 9306 person-years of observation. Using the time-dependent Cox model, the 5-year adjusted hazard ratios with 95% CI for statin treatment on all-cause, cardiovascular, and HF mortality were 0.68 (0.55-0.83), 0.67 (0.54-0.82), and 0.63 (0.51-0.79), respectively. Use of inverse-probability-of-treatment weighting resulted in estimates of 0.79 (0.65-0.96), 0.77 (0.63-0.96), and 0.77 (0.61-0.95) for statin treatment on all-cause, cardiovascular, and HF mortality, respectively, compared with no statin use.
CONCLUSIONS: Among Africans with HF, statin treatment was associated with significant reduction in mortality.
Clinical characteristics and prognosis of patients admitted for heart failure: A 5-year retrospective study of African patients

Bonsu KO, Owusu IK, Buabeng KO, Reidpath DD, Kadirvelu A

Int J Cardiol, 2017 Jul 01;238:128-135.
PMID: 28318656 DOI: 10.1016/j.ijcard.2017.03.014

BACKGROUND: Mortality associated with heart failure (HF) remains high. There are limited clinical data on mortality among HF patients from African populations. We examined the clinical characteristics, long-term outcomes, and prognostic factors of African HF patients with preserved, mid-range or reduced left ventricular ejection fraction (LVEF).

METHODS AND RESULTS: We conducted a retrospective longitudinal cohort study of individuals aged ≥18years discharged from first HF admission between January 1, 2009 and December 31, 2013 from the Cardiac Clinic, Directorate of Medicine of the Komfo Anokye Teaching Hospital, Ghana. A total of 1488 patients diagnosed of HF were included in the analysis. Of these, 345 patients (23.2%) had reduced LVEF (LVEF<40%) [HFrEF], 265(17.8%) with mid-range LVEF (40%≥LVEF<50%) [HFmEF] and 878 (59.0%) had preserved LVEF (LVEF≥50%) [HFpEF]. Kaplan-Meier curves and log-rank test demonstrated better prognosis for HFpEF compared to HFrEF and HFmEF patients. An adjusted Cox analysis showed a significantly lower risk of mortality for HFpEF (hazard ratio (HR); 0.74; 95% confidence interval (CI) 0.57-0.94) p=0.015). Multivariate analyses showed that age, higher New York Heart Association (NYHA) functional class, lower LVEF, chronic kidney disease, atrial fibrillation, anemia, diabetes mellitus and absence of statin and aldosterone antagonist treatment were independent predictors of mortality in HF. Although, prognostic factors varied across the three groups, age was a common predictor of mortality in HFpEF and HFmEF.

CONCLUSIONS: This study identified the clinical characteristics, long-term mortality and prognostic factors of African HF patients with reduced, mid-range and preserved ejection fractions in a clinical setting.
Coronary intervention door-to-balloon time and outcomes in ST-elevation myocardial infarction: a meta-analysis

Foo CY, Bonsu KO, Nallamothu BK, Reid CM, Dhippayom T, Reidpath DD, et al.

Heart, 2018 08;104(16):1362-1369.
PMID: 29437704 DOI: 10.1136/heartjnl-2017-312517

OBJECTIVE: This study aims to determine the relationship between door-to-balloon delay in primary percutaneous coronary intervention and ST-elevation myocardial infarction (MI) outcomes and examine for potential effect modifiers.
METHODS: We conducted a systematic review and meta-analysis of prospective observational studies that have investigated the relationship of door-to-balloon delay and clinical outcomes. The main outcomes include mortality and heart failure.
RESULTS: 32 studies involving 299 320 patients contained adequate data for quantitative reporting. Patients with ST-elevation MI who experienced longer (>90 min) door-to-balloon delay had a higher risk of short-term mortality (pooled OR 1.52, 95% CI 1.40 to 1.65) and medium-term to long-term mortality (pooled OR 1.53, 95% CI 1.13 to 2.06). A non-linear time-risk relation was observed (P=0.004 for non-linearity). The association between longer door-to-balloon delay and short-term mortality differed between those presented early and late after symptom onset (Cochran's Q 3.88, P value 0.049) with a stronger relationship among those with shorter prehospital delays.
CONCLUSION: Longer door-to-balloon delay in primary percutaneous coronary intervention for ST-elevation MI is related to higher risk of adverse outcomes. Prehospital delays modified this effect. The non-linearity of the time-risk relation might explain the lack of population effect despite an improved door-to-balloon time in the USA.
CLINICAL TRIAL REGISTRATION: PROSPERO (CRD42015026069).
Fulltext Review of novel therapeutic targets for improving heart failure treatment based on experimental and clinical studies

Bonsu KO, Owusu IK, Buabeng KO, Reidpath DD, Kadirvelu A

Ther Clin Risk Manag, 2016;12:887-906.
PMID: 27350750 DOI: 10.2147/TCRM.S106065

Heart failure (HF) is a major public health priority due to its epidemiological transition and the world's aging population. HF is typified by continuous loss of contractile function with reduced, normal, or preserved ejection fraction, elevated vascular resistance, fluid and autonomic imbalance, and ventricular dilatation. Despite considerable advances in the treatment of HF over the past few decades, mortality remains substantial. Pharmacological treatments including β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists have been proven to prolong the survival of patients with HF. However, there are still instances where patients remain symptomatic, despite optimal use of existing therapeutic agents. This understanding that patients with chronic HF progress into advanced stages despite receiving optimal treatment has increased the quest for alternatives, exploring the roles of additional pathways that contribute to the development and progression of HF. Several pharmacological targets associated with pathogenesis of HF have been identified and novel therapies have emerged. In this work, we review recent evidence from proposed mechanisms to the outcomes of experimental and clinical studies of the novel pharmacological agents that have emerged for the treatment of HF.

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