A Systematic Review of Cost-Effectiveness of Non-Statin Lipid-Lowering Drugs for Primary and Secondary Prevention of Cardiovascular Disease in Patients with Type 2 Diabetes Mellitus.

Although studies of nonstatin lipid-lowering therapies have demonstrated cardiovascular benefits; whether these benefits provide good value has not been evaluated in type 2 diabetes mellitus patients. A systematic review was performed to include studies on the cost-effectiveness of non-statin lipid-lowering therapies in type 2 diabetes mellitus patients with/without cardiovascular disease. Thirteen studies were included; ezetimibe (n = 8), proprotein convertase subtilisin/kexin type 9 inhibitors (n = 4), fenofibrate (n = 2), nicotinic acid (n = 1), extended-release niacin/laropiprant (n = 1), and icosapent ethyl (n = 1). Six studies considered ezetimibe + statin to be a cost-effective compared to statins monotherapy, three studies suggested that proprotein convertase subtilisin/kexin type 9inhibitors + statins were not cost-effective compared to statin + ezetimibe. Fenofibrate was a cost-effective either as monotherapy or combined with a statin compared to statin or fenofibrate monotherapy. Nicotinic acid and proprotein convertase subtilisin/kexin type 9 compared to statin monotherapy were also cost-effective. Icosapent ethyl was cost-effective compared to standard care but not using the wholesale acquisition cost.

Effectiveness of Levoamlodipine Maleate for Hypertension Compared with Amlodipine Besylate: a Pragmatic Comparative Effectiveness Study.

PURPOSE: Antihypertensive treatment is the most important method to reduce the risk of cardiovascular events in hypertensive patients. However, there is scant evidence of the benefits of levoamlodipine maleate for antihypertensive treatment using a head-to-head comparison in the real-world. This study aims to examine the effectiveness of levoamlodipine maleate used to treat outpatients with primary hypertension compared with amlodipine besylate in a real-world setting. METHODS: This was a pragmatic comparative effectiveness study carried out at 110 centers across China in outpatients with primary hypertension treated with levoamlodipine maleate or amlodipine besylate, with 24 months of follow-up. The primary outcomes used for evaluating the effectiveness were composite major cardiovascular and cerebrovascular events (MACCE), adverse reactions, and cost-effectiveness. RESULTS: Among the included 10,031 patients, there were 482 MACCE, 223 (4.4%) in the levoamlodipine maleate group (n = 5018) and 259 (5.2%) in the amlodipine besylate group (n = 5013) (adjusted hazard ratio = 0.90, 95%CI: 0.75-1.08, P = 0.252). The levoamlodipine maleate group had lower overall incidences of any adverse reactions (6.0% vs. 8.4%, P < 0.001), lower extremity edema (1.1% vs. 3.0%, P < 0.001) and headache (0.7% vs. 1.1%, P = 0.045). There was a nearly 100% chance of the levoamlodipine maleate being cost-effective at a willingness to pay threshold of 150,000 Yuan per quality-adjusted life years (QALYs) gained, resulting in more QALYs (incremental QALYs: 0.00392) and cost savings (saving 2725 Yuan or 28.8% reduction in overall costs) per patient. CONCLUSION: In conclusion, levoamlodipine maleate could reduce cost by 29% with a similar MACCE incidence rate and lower occurrence of adverse reactions (especially edema and headache) compared with amlodipine besylate. TRIAL REGISTRATION: Clinicaltrials.gov NCT01844570 registered at May 1, 2013.

Assessment of the Role of Niacin in Managing Cardiovascular Disease Outcomes: A Systematic Review and Meta-analysis.

Importance: Niacin remains a therapeutic option for patients with cardiovascular disease, but recent studies have called into question the effectiveness of other drugs that increase high-density lipoprotein cholesterol levels. Objective: To systematically review and evaluate the evidence supporting current US Food and Drug Administration-approved uses of niacin in cardiovascular disease prevention settings. Data Sources: MEDLINE, Embase, Cochrane Controlled Clinical Trial Register (Central), ClinicalTrials.gov, and TrialResults-center, from database inception to October 2017. Study Selection: The systematic review included clinical trials involving niacin as a treatment for cardiovascular disease. The meta-analysis included randomized clinical trials reporting niacin's effect, as exposure, on at least 1 long-term cardiovascular disease outcome. Data Extraction and Synthesis: Aggregate study-level data were extracted between November 2017 and January 2018 by 3 independent reviewers, and the analysis was performed in February 2018. Inverse-variance weighted methods were used to produce pooled risk ratios using random-effects models for between-study heterogeneity. Random effects-weighted metaregression analysis was used to assess the association of change in high-density lipoprotein cholesterol levels with the log risk ratio of the pooled results. Main Outcomes and Measures: Cardiovascular disease, coronary heart disease mortality, and other cardiovascular events, including acute coronary syndrome, fatal and nonfatal stroke, revascularization, and major adverse cardiac events. Results: Of 119 clinical trials, 17 documented niacin's effect on at least 1 cardiovascular disease outcome. The meta-analysis included 35 760 patients with histories of cardiovascular disease or dyslipidemia. Cumulative evidence found no preventive association of niacin with cardiovascular outcomes in secondary prevention. Stratified meta-analysis showed an association of niacin monotherapy with reduction of some cardiovascular events among patients without statin treatment (acute coronary syndrome: relative risk, 0.74; 95% CI, 0.58-0.96; stroke: relative risk, 0.74; 95% CI, 0.59-0.94; revascularization: relative risk, 0.51; 95% CI, 0.37-0.72). These results were mainly derived from 2 trials conducted in the 1970s and 1980s. Conclusions and Relevance: Niacin may have some use in lipid control for secondary prevention as monotherapy, perhaps in patients intolerant to statins, but evidence is from older studies on a population potentially not representative of current-day patients.

Effect of Combination Cholesterol-Lowering Therapy and Triglyceride-Lowering Therapy on Medical Costs in Patients With Type 2 Diabetes Mellitus.

High triglyceride (TG) levels among patients with type 2 diabetes mellitus (DM) are associated with higher medical costs. We analyzed the economic impact of TG-lowering therapies and whether the association between medical costs and therapy differed according to TG reduction. We conducted an observational cohort study of 184,932 patients with diabetes mellitus who had a TG measurement between January 2012 and June 2013 and a second TG measurement 3 to 15 months later. We identified 4 therapy groups (statin monotherapy, TG-specific monotherapy, statin/TG-specific combination therapy, or no therapy) and stratified those groups by percent change in TG (increased ≥5%, change of ≤4.9%, decreased 5% to 29%, decreased ≥30%). We compared change in medical costs between the year before and after therapy, adjusted for demographic and clinical characteristics. Of the 184,932 total patients, 143,549 (77.6%) received statin monotherapy, 900 (0.5%) received TG-specific monotherapy, 1,956 (1.1%) received statin and TG-specific combination therapy, and 38,527 (20.8%) received no prescription lipid agents. After covariate adjustment, statin/TG-specific agent recipients had a mean 1-year total cost reduction of $1,110. The greatest cost reduction was seen among statin/TG-specific combination therapy patients who reduced TG levels by ≥30% (-$2,859). Statin monotherapy patients who reduced TG by ≥30% also had a large reduction in adjusted costs (-$1,079). In conclusion, we found a substantial economic benefit to treating diabetic patients with statin/TG-specific combination lipid therapy compared with monotherapy of either type or no lipid pharmacotherapy. A TG reduction of ≥30% produced a particularly large reduction in 1-year medical costs.

Lipoprotein(a) in postmenopausal women: assessment of cardiovascular risk and therapeutic options.

INTRODUCTION: Lipoprotein(a) [Lp(a)], a low-density lipoprotein (LDL)-like particle, has been independently associated with increased cardiovascular disease (CVD) risk in various populations, such as postmenopausal women. The purpose of this narrative review is to present current data on the role of Lp(a) in augmenting CVD risk in postmenopausal women and focus on the available therapeutic strategies. METHODS: PubMed was searched for English language publications until November 2015 under the following terms: "therapy" OR "treatment" AND ["lipoprotein (a)" OR "Lp(a)"] AND ("postmenopausal women" OR "menopausal women" OR "menopause"). RESULTS: Only hormone replacement therapy (mainly oral estrogens) and tibolone have been specifically studied in postmenopausal women and can reduce Lp(a) concentrations by up to 44%, although evidence indicating a concomitant reduction in CVD risk associated with Lp(a) is lacking. As alternative treatments for women who cannot, or will not, take hormonal therapies, niacin and the upcoming proprotein convertase subtilisin / kexin type 9 (PCSK-9) inhibitors are effective in reducing Lp(a) concentrations by up to 30%. Statins have minimal or no effect on Lp(a). However, data for these and other promising Lp(a)-lowering therapies including mipomersen, lomitapide, cholesterol-ester-transfer protein inhibitors and eprotirome are derived from studies in the general, mainly high CVD risk, population, and include only subpopulations of postmenopausal women. CONCLUSIONS: Past, present and emerging therapies can reduce Lp(a) concentrations to a varying extent. Overall, it remains to be proven whether the aforementioned reductions in Lp(a) by these therapeutic options are translated into CVD risk reduction in postmenopausal women.

Effects of Vascular and Nonvascular Adverse Events and of Extended-Release Niacin With Laropiprant on Health and Healthcare Costs.

BACKGROUND: Extended-release niacin with laropiprant did not significantly reduce the risk of major vascular events and increased the risk of serious adverse events in Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), but its net effects on health and healthcare costs are unknown. METHODS AND RESULTS: 25 673 participants aged 50 to 80 years with previous cardiovascular disease were randomized to 2 g of extended-release niacin with 40 mg of laropiprant daily versus matching placebo, in addition to effective statin-based low-density lipoprotein cholesterol-lowering treatment. The net effects of niacin-laropiprant on quality-adjusted life years and hospital care costs (2012 UK £; converted into US $ using purchasing power parity index) during 4 years in HPS2-THRIVE were evaluated using estimates of the impact of serious adverse events on health-related quality of life and hospital care costs. During the study, participants assigned niacin-laropiprant experienced marginally but not statistically significantly lower survival (0.012 fewer years [standard error (SE) 0.007]), fewer quality-adjusted life years (0.023 [SE 0.007] fewer using UK EQ-5D scores; 0.020 [SE 0.006] fewer using US EQ-5D scores) and accrued greater hospital costs (UK £101 [SE £37]; US $145 [SE $53]). Stroke, heart failure, musculoskeletal events, gastrointestinal events, and infections were associated with significant decreases in health-related quality of life in both the year of the event and in subsequent years. All serious vascular and nonvascular events were associated with substantial increases in hospital care costs. CONCLUSIONS: In HPS2-THRIVE, the addition of extended-release niacin-laropiprant to statin-based therapy reduced quality of life-adjusted survival and increased hospital costs. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00461630.

The assessment of the effect of a cosmetic product brightening the skin of people with discolorations of different etiology.

BACKGROUND: Hyperpigmentations are disorders displayed with a change in the color of the skin, its strange shape, the lack of symmetry, and irregular placement. They appear no matter on the age, gender, and often as a congenital defect. Disorder connected with overproduction of melanin by pigmentary cells. The change of color is due to endogenous and exogenous cause. OBJECTIVES: The aim of this thesis was to conduct a research in vivo. This will allow to judge the effectiveness of the cosmetic product which brightens the skin with hyperpigmentation problems. The characteristics of dermocosmetics were tested on people with various etiology of hyperpigmentation. The aim of the research was to assess the effect of the active substances used daily on skin hyperpigmentation. METHODS: The tests were carried out on groups of patients with hyperpigmentations. The application of the pharmaceutical and the use of specific apparatus measurements were taken on every medical checkup. A survey was conducted to assess the changes in the face, neck, and neckline skin. The research was based on the apparatus analysis of the skin condition (MPA® , VISIA® ). RESULTS: Regular application of the pharmaceutical caused brightening of hyperpigmentations (P < 0.05). General improvement in skin condition was also observed - the increase in skin elasticity, smoothness, and the enhancement of hydration levels. CONCLUSIONS: Dermocosmetics for people with hyperpigmentation are an essential part of their medical treatment. In case of epidermal hyperpigmentation, the recipe of individually chosen and tested combination of ingredients enables us to reach satisfactory results.

Nicotinic acid treatment for Paralepistopsis acromelalga intoxication: assessment using magnetic resonance imaging.

CONTEXT: Paralepistopsis acromelalga, formerly known as Clitocybe acromelalga, is a rare poisonous mushroom. The mycotoxins in this mushroom cause symptoms resembling those of erythromelalgia; however, its pathogenesis remains unclear. In this report, a patient who received nicotinic acid treatment for P. acromelalga poisoning and radiological evaluation for erythromelalgia has been presented. Case detail: A 59-year-old woman was hospitalized for redness, swelling, and burning pain in her extremities that rendered difficulty in walking, and a diagnosis of P. acromelalga poisoning was made by detailed interview and mushroom identification. She was treated with intravenous nicotinic acid for 17 days followed by oral nicotinic acid amide for 2 months. She exhibited rapid symptomatic improvement and walked independently after 11 days of initial treatment. Initial MRI of her feet revealed toe-dominated subcutaneous thickening. After nicotinic acid treatment, those radiological findings improved dramatically. DISCUSSION: The subcutaneous thickening evident on MRI indicated P. acromelalga poisoning-induced erythromelalgia involved subcutaneous inflammatory edema. The typical duration of edema without treatment is more than a month. The improvement on MRI after nicotinic acid treatment indicated that the adequate vasodilation induced by nicotinic acid contributed to resolution of the symptoms. Nicotinic acid was associated with the improvement of the edematous changes caused by the P. acromelalga intoxication.

Trends in the Use of Nonstatin Lipid-Lowering Therapy Among Patients With Coronary Heart Disease: A Retrospective Cohort Study in the Medicare Population 2007 to 2011.

BACKGROUND: Nonstatin lipid-lowering therapy is adjunctive therapy for high-risk individuals on statins or monotherapy among those who cannot tolerate statins. OBJECTIVES: This study determined time trends between 2007 and 2011 for statin and nonstatin lipid-lowering therapy (niacin, fibrates, bile acid sequestrants, and ezetimibe) use among Medicare beneficiaries with coronary heart disease (CHD) in light of emerging clinical trial evidence. METHODS: We conducted a retrospective cohort study using the national 5% random sample of Medicare beneficiaries (n = 310,091). We created 20 cohorts of individuals with CHD, representing calendar quarters from 2007 through 2011, to assess trends in use of statins and nonstatin lipid-lowering medications. RESULTS: Statin use increased from 53.1% to 58.8% between 2007 and 2011. Ezetimibe use peaked at 12.1% and declined to 4.6% by the end of 2011, declining among both patients on statins (18.4% to 6.2%) and not on statins (5.0% to 2.4%). Fibrate use increased from 4.2% to 5.0%, bile acid sequestrants did not change significantly, and niacin use increased from 1.5% to 2.4% and then declined in late 2011. Use of nonstatin lipid-lowering therapy was less common at older age, among African Americans, patients with heart failure, and patients with a higher Charlson comorbidity score. Nonstatin lipid-lowering therapy use was more common among men and patients with diabetes, those who had cardiologist visits, and among those taking statins. CONCLUSIONS: Declining ezetimibe and niacin use but not fibrate therapy among Medicare beneficiaries with CHD coincides with negative clinical trial results for these agents.

Cardiovascular primary prevention: how high should we set the bar?

Recent trials in cardiovascular medicine have contradicted current practice, and, accordingly, are medical reversals. Extended-release niacin and fenofibrate have failed to provide mortality benefit when added to statin therapy, though both drugs have been used for this purpose for years. Cardiovascular primary prevention is no small matter. Annual spending on statins exceeded $19 billion in 2005, ezetimibe cost over $5 billion in 2007, and fenofibrate costs passed $1 billion in 2009. Given the tremendous price of these medications, and recent trials that have undermined years of practice, we propose that the bar for cardiovascular primary prevention has been raised. Large studies must show improvements in overall mortality before novel agents are recommended and used. The implications of this proposal are considered.

Cost-effectiveness of extended-release niacin/laropiprant added to a stable simvastatin dose in secondary prevention patients not at cholesterol goal in Germany.

Coronary heart disease (CHD) remains the leading cause of death in Germany despite statin use to reduce low-density lipoprotein cholesterol (LDL-C) levels; improving lipids beyond LDL-C may further reduce cardiovascular risk. A fixed-dose combination of extended-release niacin (ERN) with laropiprant (LRPT) provides comprehensive lipid management. We adapted a decision-analytic model to evaluate the economic value (incremental cost-effectiveness ratio [ICER] in terms of costs per life-years gained [LYG]) of ERN/LRPT 2 g over a lifetime in secondary prevention patients in a German setting. Two scenarios were modelled: (1) ERN/LRPT 2 g added to simvastatin 40 mg in patients not at LDL-C goal with simvastatin 40 mg; (2) adding ERN/LRPT 2 g compared with titration to simvastatin 40 mg in patients not at LDL-C goal with simvastatin 20 mg. In both scenarios, adding ERN/LRPT was cost-effective relative to simvastatin monotherapy at a commonly accepted threshold of €30,000 per LYG; ICERs for ERN/LRPT were €13,331 per LYG in scenario 1 and €17,684 per LYG in scenario 2. Subgroup analyses showed that ERN/LRPT was cost-effective in patients with or without diabetes, patients aged ≤ 65 or >65 years and patients with low baseline high-density lipoprotein cholesterol levels; ICERs ranged from €10,342 to €15,579 in scenario 1, and from €14,081 to €20,462 in scenario 2. In conclusion, comprehensive lipid management with ERN/LRPT 2 g is cost-effective in secondary prevention patients in Germany who have not achieved LDL-C goal with simvastatin monotherapy.

Dyslipidemia in the elderly: should it be treated?

Elderly or older adults constitute a rapidly growing segment of the United States population, thus resulting in an increase in morbidity and mortality related to cardiovascular disease-an increase that is reaching epidemic proportions. Dyslipidemia is a well established risk factor for cardiovascular disease and is estimated to account for more than half of the global cases of coronary artery disease. Despite the increased prevalence of dyslipidemia in the older adult population, controversy persists regarding the benefits of treatment in this group. Epidemiologic studies have shown that dyslipidemia is often underdiagnosed and under treated in this population probably as a result of a paucity of evidence regarding the impact of treatment in delaying the progression of atherosclerotic disease, concerns involving increased likelihood of adverse events or drug interactions, or doubts regarding the cost effectiveness of lipid-lowering therapy in older adults. In conclusion, despite the proven efficacy of lipid-lowering therapy in decreasing cardiovascular morbidity and mortality, these therapies have been underutilized in older patients.

Niacin and fibrate use among patients with high triglycerides and low high-density lipoprotein cholesterol.

BACKGROUND: National guidelines recommend treating low HDL and/or high triglycerides (TG) with adjunctive therapy that supplements statin monotherapy in patients with multiple cardiovascular disease (CVD) risk factors. Niacin and fibrates have been shown in clinical trials to be effective as adjunctive therapy for these lipid abnormalities. OBJECTIVE: To evaluate the pharmacologic treatment of low HDL and high TG in real-world practice by assessing a large managed-care population with CVD risk factors enrolled in a commercial health plan. RESEARCH DESIGN AND METHODS: Complete lipid panel results (LDL, HDL, TG) obtained between 1/1/2006 and 12/31/2006 (index lab) were available for all participants. Subjects were observed 180 days pre-index to determine which CVD risk factors were present (male aged 45+, female 55+, coronary heart disease, hypertension, diabetes mellitus). Patients whose LDL was at goal but who had low HDL and high TG were assessed for lipid treatment status by evaluating outpatient pharmacy claims 6 months pre- and post-index. RESULTS: Treatment with any lipid therapy increased for all risk groups, and by total risk factors, from pre-index to post-index. Use of fibrates and niacin, alone or in combination with a statin, also increased for all risk groups, and by total risk factors as well, but was below expectations based on guideline recommendations. For example, among patients with 4 risk factors, <20% of patients with low HDL/high TG received niacin and/or a fibrate post-index date. CONCLUSIONS: Our results indicate that in actual clinical practice, niacin and fibrates are underutilized in the treatment of low HDL and high TG. The findings of this study must be considered within the limitations of database analysis as claims data are collected for the purpose of payment and not research.

The impact of residual CVD risk in the managed care setting.

Pharmacoeconomic modeling studies based on real-world data from large managed care databases have been used to describe the potential effects on both cardiovascular event reduction and healthcare costs by achieving optimal lipid values. Using baseline lipid values and product labeling information, pharmacoeconomic models estimate that lipid targets are achieved more frequently with extended-release niacin/simvastatin combination therapy than with increased statin dosage. These modeling studies also estimate that extended-release niacin/simvastatin combination therapy, which modifies all lipid parameters, would reduce direct medical costs of coronary heart disease events more effectively than would high-dose statin monotherapy.

Flushing ASsessment Tool (FAST): psychometric properties of a new measure assessing flushing symptoms and clinical impact of niacin therapy.

BACKGROUND AND OBJECTIVE: A common adverse effect of niacin therapy is flushing, manifested by cutaneous warmth, redness, itching and/or tingling. The Flushing ASsessment Tool (FAST) was developed to assess flushing symptoms and their impact on patients receiving niacin therapy. This study evaluated the reliability, validity and responsiveness of the FAST. The minimal important difference (MID) of the FAST was also examined. METHODS: This was a prospective, randomized, double-blind, placebo-controlled, parallel-group 8-week study conducted to evaluate the psychometric characteristics of the FAST. The instrument is administered daily using an electronic patient diary. The study was conducted at 41 clinical sites in the US. 276 patients with dyslipidaemia were randomized to treatment and were at least 18 years of age, with fasting laboratory values of low-density lipoprotein cholesterol (LDL-C) <250 mg/dL and one of the following: high-density lipoprotein cholesterol (HDL-C) <40 mg/dL for males or <50 mg/dL for females; or triglycerides (TG) > or = 150 and < or = 400 mg/dL; or LDL-C > or = 70 mg/dL for patients with a history of coronary heart disease (CHD) or CHD risk equivalents, or > or = 100 mg/dL for subjects with two risk factors, or > or = 160 mg/dL for subjects with 0-1 risk factors. Patients were randomized (1 : 1 : 1) to receive niacin extended-release (NER) 500 mg/day in week 1, 1000 mg/day in week 2 and 2000 mg/day in weeks 3-6/aspirin (acetylsalicylic acid [ASA]), NER/ASA placebo, or NER placebo/ASA placebo. RESULTS: FAST test-retest reliability in stable patients during the first 2 weeks was demonstrated for overall flushing severity using patient and physician overall treatment effect (OTE) ratings (intraclass correlation coefficients of >0.7 for mean overall and individual flushing severity scores). Over the 6-week treatment period, FAST scores demonstrated significant correlations with individual symptoms, impact on daily activities and sleep, and dissatisfaction related to flushing (p < 0.01). Changes in FAST scores were associated with treatment satisfaction (p < 0.01) and patient- and physician-rated OTE (p < 0.01). Using patient-rated OTE, the mean maximum flushing severity scores improved 1.85 points in responders and only 0.18 points in non-responders (p < 0.001); responders were defined by improved patient- or physician-rated OTE. Among patients with flushing, mean maximum overall flushing scores differed between patients who subsequently discontinued due to flushing (7.9 points) and those who did not discontinue (4.7 points; p < 0.001). The probable range in this study for a detectable change in flushing symptoms (MID) was 0.29-0.38 points for mean flushing severity and 0.66-0.86 points for maximum flushing severity. CONCLUSION: The FAST exhibited test-retest reliability, good evidence of construct validity, and, overall, flushing severity was responsive to change over time. The FAST is a reliable and valid instrument for assessing the impact of niacin-induced flushing in patients with dyslipidaemia.

Niacin and analogs for phosphate control in dialysis--perspective from a developing country.

Hyperphosphatemia is an important modifiable risk factor in the dialysis population because it is linked to increased mortality. Existing phosphate-reducing agents either increase the risk of vascular calcification or are costly with high pill burden. Niacin shows promise as a cheap drug with low pill burden and a novel mode of action. Niacin and its metabolite nicotinamide inhibit the small intestinal sodium-phosphate cotransporter. Approximately 50% of intestinal phosphate absorption occurs through this route under physiological conditions. Studies performed on the dialysis population with niacin and nicotinamide have shown significant phosphate reduction with lowering of the calcium-phosphorus product. The well documented increase in serum HDL levels may also offer survival benefits. Side-effects include flushing, which is controlled with aspirin, diarrhea, and thrombocytopenia, which may be treatment-limiting. Niacin is cheap and phosphate reduction can be achieved by administration of one or two tablets per day. These factors will boost compliance in developing countries. Further basic research and large-scale clinical trials are needed in this field.