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Abstract

Early high-dose statin therapy to reduce low-density lipoprotein cholesterol (LDL-C) is associated with improved cardiovascular outcomes in Western patients with stable coronary heart disease or acute coronary syndromes (ACS), but many patients remain undertreated and do not attain LDL-C treatment goals. Early statin therapy has also been shown to improve cardiovascular outcomes in Japanese patients with ACS, and pretreatment with high-dose statin prior to percutaneous coronary intervention has been shown to reduce cardiovascular events in these patients. As is the case in Western populations, many Japanese patients may be undertreated and a residual cardiovascular risk remains. While differences in treatment practice, dosing and genetic factors exist between Japan and Western countries, similarities are also evident when Japanese statin studies are compared with those performed in Western populations. With the increasing prevalence of cardiovascular risk factors in Japan, aggressive statin treatment may be beneficial in achieving optimal cardiovascular outcomes.

Keywords

Acute coronary syndrome cardiovascular risk Japan low-density lipoprotein cholesterol statin

Introduction

Intensive statin therapy reduces cardiovascular (CV) risk in patients with stable coronary heart disease (CHD)¹ or following acute coronary syndromes (ACS).^2,3 The lowering of low-density lipoprotein cholesterol (LDL-C) with statins reduces CV risk to a similar extent in patients with low baseline cholesterol levels (<80 mg/dl) as it does in those with higher baseline levels.⁴ For example, statin therapy was associated with improved outcomes in Korean patients with acute myocardial infarction (AMI) and LDL-C <70 mg/dl.⁵ Large clinical trials of statins in Western populations with ACS have reported significant early reductions in CV events.^3,6 These early benefits may be independent of LDL-C reduction, suggesting the involvement of cholesterol-independent (pleiotropic) effects of statins.^7–10 These pleiotropic effects may be relevant to all patients, regardless of their baseline LDL-C levels.¹⁰

European and US guidelines, developed from expert opinion of trials in Western populations, recommend that patients with ACS begin statin therapy before hospital discharge, with a long-term LDL-C goal of <100 mg/dl and an option of extending to <70 mg/dl.^11,12 Japanese guidelines, based on specialist opinion, have set a value of <100 mg/dl as the therapeutic target for LDL-C, in patients with ACS.¹³

The early benefits of aggressive LDL-C reduction with statins have been well demonstrated in Western populations with ACS. Evidence is less clear in Japanese populations, however, and ACS outcomes and optimum treatment may differ from those reported in Western populations. This review sought to assess whether conclusions derived from safety and efficacy studies in Western populations are relevant to Japanese patients with ACS.

Epidemiology

The lower incidence of CHD in Japan compared with Western countries may be partly explained by lower cholesterol levels, but other environmental or genetic factors may also influence these rates.^14,15 The variation in ACS morbidity and mortality between Japanese and Western populations may be explained by differences in social healthcare systems, including use of interventional procedures and differences such as race, diet, lifestyle and use of evidence-based medications.¹⁶

The INTERHEART study was a case–control study of myocardial infarction (MI) that assessed the importance of CHD risk factors in 52 ethnically diverse countries.¹⁷ The majority of MI risk was accounted for by abnormal lipid levels, smoking, hypertension, diabetes, abdominal obesity, psychosocial factors, consumption of fruits, vegetables and alcohol, and regular physical activity. These risk factors were consistent across ethnic groups and geographical locations.¹⁷

Historically, Japan has had a unique profile of CV risk, with a relatively low incidence of CHD but a high incidence of stroke compared with the USA.^18,19 The mortality rate for stroke has declined, leaving CHD as a more common cause of death in Japan.¹⁹ In addition, there is concern that Westernisation of lifestyles may increase CHD risk.²⁰ Lifestyle modifications (including diet and smoking cessation) could help to mitigate part of the CHD risk but, as observed in Western countries, the residual risk will depend on absolute levels of risk factor control achieved.

In Western populations, elevated cholesterol levels have been shown to be one of the most important modifiable risk factors for CHD,^21,22 and high cholesterol is also associated with an increased risk of CHD in Japan.^23,24 General increases in total cholesterol (TC) levels were reported between 1960 and 2000 in Japan, for both sexes and in almost all generations.²⁵ A study including 9216 Japanese participants aged ≥30 years reported that a high baseline TC (≥260 mg/dl) was associated with a 3.81-fold increased risk of CHD and a 1.36-fold increased risk of all-cause mortality, compared with the median TC (160–180 mg/dl).²⁴

The Framingham Heart study, which is a longitudinal population-based cohort, assesses the risk factors and consequences of arteriosclerotic and hypertensive CV disease in the USA. It was established in 1948 and has continued to observe the first- and second-generation offspring of the original participants.²⁶ Another long-term, prospective cohort study of CV disease was established in Hisayama, Japan.²⁷ Comparison of the data from these two studies revealed that MI rates were five to six times higher in the Framingham population than in Hisayama, but cerebral infarction rates were three to four times higher in the Hisayama population than in Framingham (Figure 1).²⁷

Figure 1.

Comparison of the incidences of (A) myocardial infarction and (B) cerebral infarction in the Hisayama and Framingham studies²⁷

Cardiovascular events

Efficacy (aggressive treatment)

Western data

The Cholesterol Treatment Trialists (CTT) Collaboration carried out a meta-analysis of five randomised trials of statins that compared more intensive (higher dose or more powerful statin) and less intensive (lower dose or less powerful statin) regimens, in 39 612 patients with ACS or stable coronary disease.⁴ The efficacy and safety of intensive LDL-C lowering with statins was assessed. The overall benefit was similar to that observed in statin versus placebo trials. Intensive statin treatment was associated with a greater reduction in major vascular events compared with less intensive therapy, and the risk of first major vascular events was reduced by ∼20% per 1 mmol/l reduction in LDL-C. This benefit was not limited to patients with elevated cholesterol levels at baseline and no threshold was found under which LDL-C lowering was no longer beneficial (including baseline LDL-C <80 mg/dl).⁴

Intensive lipid lowering with statins following ACS was assessed in two large trials: the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 (PROVE IT–TIMI 22) trial compared atorvastatin with pravastatin;² phase Z of the Aggrastat® to Zocor® (A to Z) trial examined the effect of intensive versus conservative simvastatin regimens following an ACS event.²⁸ When data from A to Z and PROVE IT–TIMI 22 were pooled, intensive statin therapy was found to lower the risk of all-cause mortality significantly, compared with moderate statin therapy (hazard ratio [HR] 0.77, 95% confidence intervals [CI] 0.63, 0.95).²⁹

The PROVE IT–TIMI 22 trial investigated the effect of intensive versus moderate statin therapy on the incidence of death or major cardiovascular events in patients with ACS.^2,30 Patients who had been hospitalised for ACS were randomised to receive atorvastatin 80 mg/day or pravastatin 40 mg/day, and were followed for ∼24 months. The primary endpoint was a composite of all-cause death, MI, unstable angina requiring hospitalisation, revascularisation (≥30 days after randomisation) and stroke. Atorvastatin treatment was associated with significantly lower LDL-C levels, and reduction in risk of both CV and the composite primary endpoint, compared with pravastatin treatment.²

In PROVE IT–TIMI 22, the benefits of atorvastatin therapy were evident within 30 days of randomisation (Figure 2).⁶ In the first 30 days, the LDL-C levels of patients who were statin-naïve at randomisation were reduced by 22% in the pravastatin group and by 51% in the atorvastatin group (P <0.0001). An analysis assessing the timing of CV benefit from intensive statin therapy at 30 days demonstrated a lower risk of events with intensive therapy, such that 3.0% of atorvastatin-treated patients and 4.2% of pravastatin-treated patients experienced a primary endpoint event (HR 0.72, 95% CI 0.52, 0.99).⁶ Intensive statin assignment was associated with less target vessel revascularisation than standard therapy in participants who underwent percutaneous coronary intervention (PCI) before enrolment, even after adjusting for LDL-C and C-reactive protein (CRP). As this benefit was still evident after adjusting for LDL-C, these results suggest that a cholesterol-independent treatment effect may be involved.³¹ Additional examination of the relationship between 30-day LDL-C and CRP levels, and MI or coronary death, reported that patients with low CRP levels had fewer recurrent events regardless of their LDL-C levels:³² this finding implicates inflammation (or residual inflammation) in the pathogenesis of recurrent coronary events. Furthermore, a cross-sectional study of PROVE IT–TIMI 22 found that intensive statin therapy was associated with lower CRP levels, regardless of other risk factors.³³ This analysis also found that patients with fewer coronary risk factors had lower CRP levels, suggesting that addressing these risk factors could lower CRP levels further.³³

Figure 2.

PROVE IT–TIMI 22: Kaplan–Meier estimates of the composite endpoint of death, myocardial infarction (MI), or rehospitalisation with recurrent acute coronary syndrome (ACS) by statin treatment (40 mg/day pravastatin or 80 mg/day atorvastatin), from randomisation to 30 days⁶

Potential effects of different statin doses were examined in the A to Z trial, which compared early (intensive) simvastatin versus late (less intensive) simvastatin therapy. Following an ACS event, patients were randomised to receive 40 mg/day simvastatin for 1 month, then simvastatin 80 mg/day thereafter, or placebo, for 4 months, followed by simvastatin 20 mg/day; patients were followed up for ∼24 months. The primary endpoint was a composite of CV death, nonfatal MI, readmission for ACS, and stroke. After 1 month, the reduction in LDL-C in the early (intensive) arm was significantly greater than that in the late (less intensive) arm, but this benefit did not extend to a significant reduction in clinical events overall. There was no significant difference in the risk of the primary composite endpoint between treatment arms up to month 4, but from 4 months until the end of the study, the rate of the primary endpoint was significantly reduced in the early intensive arm (HR 0.75, 95% CI 0.60, 0.95).²⁸

In A to Z, intensive statin therapy in the first 4 months was associated with a 60 mg/dl difference in LDL-C, but no significant reduction in early clinical events.²⁸ This in contrast to the findings of PROVE IT–TIMI 22, where a smaller (32 mg/dl) LDL-C difference was associated with a significant reduction in early clinical events, for intensively-treated patients.⁶ The lack of consistent correlation between LDL-C and clinical event reduction in A to Z and PROVE IT–TIMI 22 could imply that statin therapy following ACS reduces clinical events in part by pleiotropic effects, and that these effects may not be consistent within the statin class. In PROVE IT–TIMI 22, the clinical benefit of atorvastatin 80 mg/day over pravastatin 40 mg/day was significant after 30 days. This is in contrast to reductions in LDL-C via nonstatin therapies that can take several years to show clinical effect,³⁴ and to trials of stable CHD patients (where the benefits may take 1–2 years to become evident).³⁵ This suggests that the statin-associated reduction in clinical events in patients with ACS may be partly mediated by cholesterol-independent mechanisms that take effect sooner than LDL-C reduction.¹⁰

Japanese data

A retrospective study³⁶ that assessed the efficacy of lipid-lowering regimens and lipid-goal attainment rates for 24 893 patients with hyperlipidaemia, under the care of 2540 physicians in Japan, reported that the majority of high-risk patients did not achieve the lipid-management goals recommended by the Japan Atherosclerosis Society in 2002.³⁷ These results suggest that much more needs to be done to achieve evidence-based goals in patients at high risk of CHD as there is currently inadequate attainment of TC, LDL-C and triglyceride goals, and therefore a significant and modifiable residual risk.³⁶

Efficacy (early treatment)

Western data

The benefits of early intensive statin treatment for patients with ACS have been demonstrated in Western populations. For example, the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial randomised 3086 (mostly Caucasian [86%] male [65%]) participants to atorvastatin 80 mg/day or placebo within 4 days of hospital admission for ACS, and demonstrated an early benefit of statin treatment.³ At 16 weeks, a significant (16%) decrease in the primary endpoint was reported for patients receiving atorvastatin, compared with those on placebo (relative risk 0.84, 95% CI 0.70, 1.00).³ Interestingly, this reduction in primary events was unrelated to baseline LDL-C, and there was no significant association between LDL-C reduction and the occurrence of the primary endpoint in patients treated with atorvastatin.³ The early benefit in MIRACL was similar to that observed in PROVE IT–TIMI 22, suggesting that pleiotropic effects could partially explain this early clinical benefit. An assessment of the effect of high-dose atorvastatin on inflammation markers in MIRACL found that such therapy significantly reduced the levels of CRP and serum amyloid A, but not interleukin-6, compared with placebo.⁷ This atorvastatin therapy-associated decline in inflammation may contribute towards the clinical benefit, in ACS patients.

The Atorvastatin for Reduction of Myocardial Damage During Angioplasty (ARMYDA-ACS) study assigned ACS patients to 80 mg atorvastatin 12 h before PCI and a further 40 mg after, or placebo. Acute atorvastatin before PCI had a protective effect, with a significant reduction in the risk of major cardiac events being observed after 30 days (odds ratio 0.12, 95% CI 0.05, 0.5).³⁸ A subsequent trial, ARMYDA-RECAPTURE, demonstrated the protective effect of acute atorvastatin before PCI, regardless of whether patients were chronic statin users; this supports the use of high-dose atorvastatin before PCI procedures, regardless of existing statin use.³⁹

Japanese data

As the prevalence of CV risk factors (including dyslipidaemia) is rising in Japan,²⁵ there has been a corresponding increased interest in studies that aim to assess the efficacy of CV risk-reduction treatments. An extension of the Early Statin Treatment in Patients with Acute Coronary Syndrome trial (Extended-ESTABLISH) demonstrated that early atorvastatin treatment (20 mg/day) improved outcomes for patients with ACS (Figure 3A).⁴⁰ Within 48 h of an ACS event and after PCI, patients were randomised to receive 20 mg/day atorvastatin or usual care for 6 months, after which all patients were treated with statins to a goal LDL-C of <100 mg/dl. After ∼4 years, early statin treatment was a significant predictor of major adverse cardiac and cerebrovascular events (HR 0.46, 95% CI 0.23, 0.86) (Figure 3B), and the benefits of early statin therapy were more notable for patients with baseline LDL-C ≥118 mg/dl.⁴⁰

Figure 3.

(A) Summary of follow-up study of Extended-ESTABLISH trial. (B) Kaplan–Meier estimates of incidence of major adverse cardiac and cerebrovascular events. Cumulative event-free survival is significantly higher in atorvastatin than control group (log-rank test, P = 0.041)⁴⁰

When Extended-ESTABLISH patients were stratified according to Japanese guidelines into those with LDL-C < 100 mg/dl (n = 54) and those with LDL-C ≥100 mg/dl (n = 124), a post hoc analysis revealed that major adverse cardiac and cerebrovascular events were reduced after 1 year of statin treatment in the ≥ 100 mg/dl group, but not in the <100 mg/dl group. There was insufficient power to determine whether there was a significant difference between groups, however.⁴¹

A further analysis of the Extended-ESTABLISH trial investigated the prognostic value of plaque regression (observed after 6 months) on clinical outcome.⁴² Patients were stratified into plaque regression (n = 55) and plaque progression (n = 31) groups, according to changes in plaque volume. Event-free survival was significantly more likely in the plaque regression group than in the progression group, and plaque regression after 6 months was a predictor of CV events (HR 0.26, 95% CI 0.07, 0.83).⁴² Given the association between LDL-C and progression/regression of atheroma, these data support the concept that achieving lower levels of LDL-C is as relevant to Japanese populations as it is to Western populations.⁴³

Surrogate endpoints

Western data

Conducting outcome trials with morbidity and mortality endpoints is statistically challenging and cost intensive, requiring many patients to be followed over several years. Using surrogate endpoints allows the effect of lipid lowering with statins to be studied with smaller sample sizes over shorter time periods, given the close relationship between LDL-C and outcomes. For these studies to be meaningful, a relationship between surrogate endpoints and clinical outcomes should be established. PROVE IT–TIMI 22 demonstrated the CV benefits of atorvastatin over pravastatin therapy. The Reversing Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial used the same treatment assignments, studying the effect of lipid lowering (with 40 mg/day pravastatin or 80 mg/day atorvastatin) on changes in atheroma, measured by intravascular ultrasound in patients with a history of CHD.⁴⁴ After 18 months, atheroma volume was increased in patients in the pravastatin group and reduced in those in the atorvastatin group.⁴⁴ The final mean LDL-C levels were 78.9 mg/dl in the atorvastatin group and 110.4 mg/dl in the pravastatin group, which was a significant difference. For any given LDL-C level there appeared to be greater reduction in atheroma burden with atorvastatin than with pravastatin. In addition, there was a large, significant, between-group difference in CRP reduction (−5.2% for pravastatin vs –36.4% for atorvastatin). The authors suggested that the differences in atherosclerosis progression could be attributed to a reduction in atherogenic lipoproteins and CRP.⁴⁴

The Study of Coronary Atheroma by Intravascular Ultrasound: effect of Rosuvastatin versus Atorvastatin (SATURN) trial examined changes in atheroma volume in high-risk patients with CHD, intensively treated with 80 mg/day atorvastatin or 40 mg/day rosuvastatin.⁴⁵ Atorvastatin and rosuvastatin were found to have similar effects on atheroma volume after 2 years.⁴⁶ Changes in lipids and CRP levels, although statistically significant, were not clinically meaningful with respect to the impact on atheroma.

Japanese data

A study in Japanese patients with ACS assessed the effects of statin treatment on plaque regression. The ESTABLISH trial randomised 70 patients with ACS to 20 mg/day atorvastatin or usual care.⁴⁷ After 6 months, atorvastatin resulted in a 41.7% reduction in LDL-C compared with a 0.7% decrease in the control group (Figure 4A). In addition, there was a significant reduction in plaque volume in the atorvastatin group and a significant increase in plaque volume in the control group (Figure 4B).⁴⁷

Figure 4.

The ESTABLISH trial.⁴⁷ (A) Low-density lipoprotein-cholesterol (LDL-C) levels and plaque volume were significantly reduced by statin treatment.⁷¹ (B) Intravascular ultrasound images before treatment (left panels) and after 6 months (right panels). Atorvastatin (lower right panel) has significantly reduced plaque area whereas no change in the plaque area can be seen in control (upper right panel)⁴⁷

Safety

Statins are believed to be associated with musculoskeletal adverse events, but are generally well tolerated in most patients.⁴⁸ Concerns have been raised regarding the impact of reducing LDL-C to very low levels with statins.⁴⁹ A safety analysis, using data from 21 atorvastatin clinical trials, found that the frequency of treatment-associated adverse events in a subgroup of patients with one or more LDL-C value ≤80 mg/dl (n = 319) was similar to that in all atorvastatin-treated patients (n = 2502).⁵⁰

The safety of intensive LDL-C lowering with statins was assessed in the CTT2 meta-analysis, which found intensive statin treatment regimens to be effective, with a good safety profile.⁴ Intensive statin treatment had no apparent effect on nonvascular mortality (including deaths from cancer, respiratory disease, trauma or all other nonvascular causes), even at low LDL-C levels. A nonsignificant increase in haemorrhagic stroke was reported in more aggressively treated patients, however.⁴ Further intensive lipid lowering with statins was not associated with an increase in adverse events, in patients with a low baseline LDL-C (<77 mg/dl).⁴

An extensive safety analysis of atorvastatin (using pooled data from 44 trials, with doses in the 10–80 mg/day range and mainly Caucasian participants), found that treatment-associated adverse events did not increase with dose.⁵¹ In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, which compared 80 mg/day atorvastatin with placebo in patients with a history of stroke or transient ischaemic attack, haemorrhagic strokes were more frequent in those treated with atorvastatin, those with a haemorrhagic stroke entry event, men and older participants.⁵²

Japanese population

Genetic and dietary differences between Japanese and Western populations may affect the safety of statins. Recommended doses of statins are generally much lower in Japan than in the USA.⁵³ For instance, in Japan, the maximum dose of atorvastatin is 20 mg/day or 40 mg/day in patients with familial hypercholesterolaemia, whereas the maximum dose used in the USA is 80 mg/day. In Japan, there are limited up-to-date epidemiological data on the state of treatment following ACS, but the Prevention of Atherothrombotic Incidents Following Ischemic Coronary Attack (PACIFIC) Registry is being analysed and will give insight into the Japanese epidemiology of ACS.⁵⁴

The Japan Cholesterol Lowering Atorvastatin Study (J-CLAS) reported that atorvastatin reduced LDL-C in a significantly dose-dependent manner, while the incidences of clinical abnormalities and side-effects were not dose dependent.⁵⁵ Observational studies in Japanese populations of patients with a history of CHD or acute MI have found that those on statins had lower all-cause and CV mortality compared with those not administered statins.^56–58 In the CREDO-Kyoto registry, patients with CHD who were discharged on statins had significantly better crude stroke-free survival rates, but statin therapy did not independently predict stroke.⁵⁸

Conclusions

Statin treatment has been shown to provide early CV event reductions in both Japanese⁵⁹ and Western^6,7 patients. In studies in Japan, the benefit was greater for patients with ACS who had elevated cholesterol levels at baseline.^41,60 Statins have also been shown to provide benefit to patients undergoing PCI, significantly reducing CV events in those who received acute pretreatment with a statin.³⁸

The benefits of statin therapy in patients with ACS were shown to occur early and may be independent of lipid lowering.^3,6 The Extended-ESTABLISH trial demonstrated that 20 mg/day atorvastatin significantly reduced the risk of CV outcomes within 1 year, compared with standard care.⁴¹ Data have also shown that statins may differ in terms of the degree of early benefit attained in patients with ACS,^2,3,28 suggesting that the regimen may be relevant.

Reduced inflammation seems to be a key non lipid-dependent effect, driving the early benefits. Markers for inflammation are related to cardiovascular events in patients with ACS,³² and studies in Western populations have revealed that statins significantly reduce serum levels of CRP, which is a nonspecific marker of inflammation.^2,61 In Chinese patients with ACS, early fluvastatin therapy dose-dependently reduced serum concentrations of CRP and tumour necrosis factor-α.⁶²

Implications

Although there are many similarities between statin studies in patients with ACS in the West compared with Japan, there are also many differences. For example, the rates of invasive treatments (such as PCI or coronary artery bypass graft following ACS) are higher in Japan than in historical cohorts from Global and Western studies.^16,63–66 However, in some Western countries, PCI usage rates are currently similar to those in Japan.^16,67 In addition to differences in treatment practice between Western countries and Japan, there are other key considerations relating to statin treatment for Japanese patients with ACS. Genetic factors relating to lipid metabolism or predisposition to other CV risk factors may lead to differences in statin treatment response in ACS clinical trials in Japan, compared with trials conducted in Western populations.^68,69 Differences in statin dosing may also be a factor.⁵³

In Japanese patients, lower doses of statins have been shown to have similar effects to those observed with higher doses of statins in Western patients.⁷⁰ What may be considered a moderate statin dose in Western patients may be considered a relatively intensive dose in Japan, and direct comparisons between doses used in Western and Japanese studies may not be possible.

Despite the apparent differences in dose requirements between Western and Japanese patients with ACS it is clear that, in both populations, optimal treatment outcomes may be achieved by more intensive and earlier treatment than by less intensive or later treatment. Further studies in Japanese patients with ACS may be required, in order to determine the optimum statin treatment regimen.

Footnotes

Declaration of conflicting interest

Dr Katsumi Miyauchi has received honoraria for lectures from Astra Zeneca, Pfizer, Merck Sharp and Dohme, Daiichi Sankyo, Novartis, Kowa, Sanofi, Takeda, Shionogi and Astellas. Professor Kausik Ray has received honoraria for lectures from Astra Zeneca, Pfizer, Roche, Merck Sharp and Dohme, Daiichi Sankyo, Abbott, Novartis, Novo Nordisk, Kowa, Sanofi and research support from Pfizer, Sanofi and Bristol-Myers Squibb.

Funding

Editorial support for the development of this manuscript was funded by Pfizer Inc., New York, USA.

Acknowledgements

Editorial support was provided by Simon Richards, PhD, of UBC Scientific Solutions Ltd (Horsham, UK).

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A review of statin use in patients with acute coronary syndrome in Western and Japanese populations

Abstract

Keywords

Introduction

Epidemiology

Cardiovascular events

Efficacy (aggressive treatment)

Western data

Japanese data

Efficacy (early treatment)

Western data

Japanese data

Surrogate endpoints

Western data

Japanese data

Safety

Japanese population

Conclusions

Implications

Footnotes

Declaration of conflicting interest

Funding

Acknowledgements

References