The Social, Demographic, and Clinical Predictors of COVID-19 Severity: a Model-based Analysis of United States Veterans.

PURPOSE: This study aims to identify the contributions of individual and community social determinants of health (SDOH), demographic, and clinical factors in COVID-19 disease severity through a model-based analysis. METHODS: This national cross-sectional study focused on hospitalization among those tested for COVID-19 and use of intensive care, analyzing data on 220,848 Veterans tested between February 20, 2020 and October 20, 2021. Multiple logistic regression models were constructed using backwards elimination. The predictive value of each model was assessed with a c-statistic. RESULTS: Those hospitalized were older, more likely to be male, of Black or Asian race, have an income less than $39,999, live in an urban residence, and have medical comorbidities. The strongest predictors for hospitalization included Gini inequality index, race, income, heart failure, chronic kidney disease (CKD), and chronic obstructive pulmonary disease (COPD). For intensive care, Asian race, rural residence, COPD, and CKD were the strongest predictors. C-statistics were c = 0.749 for hospitalization and c = 0.582 for ICU admission. CONCLUSIONS: A combination of clinical, demographic, individual and community SDOH factors predict COVID-19 hospitalization with good predictive ability and can inform risk stratification, discharge planning, and public health interventions. Racial disparities were not explained by social or clinical factors. Intensive care models had low discriminative power and may be better explained by other characteristics.

What interventions should we implement in England's mental health services? The mental health implementation network (MHIN) mixed-methods approach to rapid prioritisation.

Introduction: Setting mental health priorities helps researchers, policy makers, and service funders improve mental health services. In the context of a national mental health implementation programme in England, this study aims to identify implementable evidence-based interventions in key priority areas to improve mental health service delivery. Methods: A mixed-methods research design was used for a three step prioritisation approach involving systematic scoping reviews (additional manuscript under development), expert consultations and data triangulation. Groups with diverse expertise, including experts by experience, worked together to improve decision-making quality by promoting more inclusive and comprehensive discussions. A multi-criteria decision analysis (MCDA) model was used to combine participants' varied opinions, data and judgments about the data's relevance to the issues at hand during a decision conferencing workshop where the priorities were finalised. Results: The study identified mental health interventions in three mental health priority areas: mental health inequalities, child and adolescent mental health, comorbidities with a focus on integration of mental and physical health services and mental health and substance misuse problems. Key interventions in all the priority areas are outlined. The programme is putting some of these evidence-based interventions into action nationwide in each of these three priority mental health priority areas. Conclusion: We report an inclusive attempt to ensure that the list of mental health service priorities agrees with perceived needs on the ground and focuses on evidence-based interventions. Other fields of healthcare may also benefit from this methodological approach if they need to make rapid health-prioritisation decisions.

A Multicriteria Decision Analysis Comparing Pharmacotherapy for Chronic Neuropathic Pain, Including Cannabinoids and Cannabis-Based Medical Products.

Background: Pharmacological management of chronic neuropathic pain (CNP) still represents a major clinical challenge. Collective harnessing of both the scientific evidence base and clinical experience (of clinicians and patients) can play a key role in informing treatment pathways and contribute to the debate on specific treatments (e.g., cannabinoids). A group of expert clinicians (pain specialists and psychiatrists), scientists, and patient representatives convened to assess the relative benefit-safety balance of 12 pharmacological treatments, including orally administered cannabinoids/cannabis-based medicinal products, for the treatment of CNP in adults. Methods: A decision conference provided the process of creating a multicriteria decision analysis (MCDA) model, in which the group collectively scored the drugs on 17 effect criteria relevant to benefits and safety and then weighted the criteria for their clinical relevance. Findings: Cannabis-based medicinal products consisting of tetrahydrocannabinol/cannabidiol (THC/CBD), in a 1:1 ratio, achieved the highest overall score, 79 (out of 100), followed by CBD dominant at 75, then THC dominant at 72. Duloxetine and the gabapentinoids scored in the 60s, amitriptyline, tramadol, and ibuprofen in the 50s, methadone and oxycodone in the 40s, and morphine and fentanyl in the 30s. Sensitivity analyses showed that even if the pain reduction and quality-of-life scores for THC/CBD and THC are halved, their benefit-safety balances remain better than those of the noncannabinoid drugs. Interpretation: The benefit-safety profiles for cannabinoids were higher than for other commonly used medications for CNP largely because they contribute more to quality of life and have a more favorable side effect profile. The results also reflect the shortcomings of alternative pharmacological treatments with respect to safety and mitigation of neuropathic pain symptoms. Further high-quality clinical trials and systematic comprehensive capture of clinical experience with cannabinoids is warranted. These results demonstrate once again the complexity and multimodal mechanisms underlying the clinical experience and impact of chronic pain.

A multi criteria decision analysis (MCDA) for evaluating and appraising government policy responses to non medical heroin use.

BACKGROUND: Globally, non-medical heroin use is generating significant public health and social harms, and drug policy about heroin is a controversial field that encompasses many complex issues. Policy responses to illegal heroin markets have varied from militarized eradication of the opium poppy and harsh punishment of users, to more tolerant harm reduction approaches with decriminalized possession and use. METHODS: This paper reports the outcomes of a multi-criteria decision analysis (MCDA) on four generic regulatory regimes of heroin: prohibition, decriminalisation, state control and free market. Invited experts on drug harms, addiction, criminology and drug policy developed a comprehensive set of 27 policy outcome criteria against which these drug policy regimes were assessed. RESULTS: State control of heroin was identified as the preferred policy option although other policy regimes scored better on specific outcome criteria. The free market model scored better than decriminalisation, with absolute prohibition scoring worst on every criterium. The ranking of the regimes was robust to variations in the criterion-specific weights. CONCLUSION: The implications of these findings for the development of future policy responses to heroin and opioids generally are discussed in detail. Despite increasing overdose deaths and an opioid epidemic in North America, prohibition remains the predominant policy approach to heroin regulation at present. It is hoped that the current paper adds to the discussion of finding a valid regulatory alternative.

Multi-Criteria Decision Analysis for Benefit-Risk Analysis by National Regulatory Authorities.

The approval process for pharmaceuticals has always included a consideration of the trade-offs between benefits and risks. Until recently, these trade-offs have been made in panel discussions without using a decision model to explicitly consider what these trade-offs might be. Recently, the EMA and the FDA have embraced Multi-Criteria Decision Analysis (MCDA) as a methodology for making approval decisions. MCDA offers an approach for improving the quality of these decisions and, in particular, by using quantitative and qualitative data in a structured decision model to make trade-offs in a logical, transparent and auditable way. This paper will review the recent use of MCDA by the FDA and EMA and recommend its wider adoption by other National Regulatory Authorities (NRAs) and the pharmaceutical industry.

So near yet so far: why won't the UK prescribe medical cannabis?

Although cannabis-based products for medicinal use are now legal in the UK, it is still challenging for patients to gain access, and only very few National Health Service prescriptions have been written to date. This paper attempts to make sense of why the UK lags behind so many other countries which also have legalised medical cannabis. From consulting with parents and patients, prescribers, pharmacists and decision-makers it seems that there are a series of distinct barriers to prescribing that need to be overcome in order to improve patient access to medical cannabis in the UK. These include concerns about the perceived lack of scientific evidence. To alleviate these concerns, we highlight the importance of patient-centred approaches including patient-reported outcomes, pharmacoepidemiology and n=1 trials, which can contribute to the development of the evidence base for medical cannabis. We hope that this paper will help policymakers and prescribers understand the challenges to prescribing and so help them develop approaches to overcome the current situation which is detrimental to patients.

ICER Value Framework 2020 Update: Recommendations on the Aggregation of Benefits and Contextual Considerations.

The Institute for Clinical and Economic Review (ICER) in the United States recently published a 2020 update to its value assessment framework. We are commenting on the method by which the benefits of health interventions are integrated, relating to contextual considerations and other factors relevant to an intervention's value. We start by discussing the theoretical foundations of decision analysis and its extension to multiple criteria decision analysis (MCDA). Then we provide a detailed, evidence-based response to some of the claims made by ICER with regard to the use of MCDA methods and stakeholder engagement. Finally, we provide a number of recommendations on the use of quantitative decision analysis and decision conferencing that could be of relevance to the ICER methodology. Overall, we agree that some of the proposed changes by ICER are moving in the right direction toward improving transparency in the value assessment process, but these changes are probably inadequate. We advocate that more serious attention should be paid to the use of quantitative decision analysis together with decision conferencing for the construction of value preferences via group processes for the integration of an intervention's various benefit components.

Multi-Criteria Decision Analysis to Develop an Efficacy-Safety Profile of Parenteral Analgesics Used in the Treatment of Postoperative Pain.

BACKGROUND: Identifying the optimal treatment in an acute postoperative setting remains a challenge. Multiple analgesic options are available, but comparing outcomes is limited by a lack of head-to-head trials. In addition, decisions based on efficacy only do not take drug safety into account. In such cases, multi-criteria decision analysis (MCDA) can be utilized to quantify and compare the efficacy and safety data of various drugs. METHODOLOGY: The efficacy-safety profiles of eight parenteral, postoperative analgesics (acetaminophen, diclofenac, ketorolac, metamizole, morphine, nefopam, parecoxib, tramadol) widely used in Europe were evaluated using an MCDA model that included 17 criteria: three for efficacy and 14 for safety. Each drug was scored on each criterion on a scale from 0 (worst) to 100 (best), according to published data and the judgment of an expert panel. A weighting process was then applied to standardize the impact of each criterion and adjust drugs' preference scores accordingly, normalizing them on the 0-100 scale. Sensitivity analyses were also performed, including a model in which analgesic profiles were compared when opioid sparing effect was set at a zero value for all drugs. RESULTS: In the primary model, efficacy and safety had relative weightings of 64% and 36%, respectively. Efficacy and safety criteria with the highest values were pain relief (relative weight, 29%) and gastrointestinal effects (12%). Parecoxib received the highest overall score (93), followed by diclofenac (80), and ketorolac (75). Morphine scored the lowest (57), due to the lack of an opioid sparing effect. When opioid sparing was given a zero rating, parecoxib remained the highest scoring analgesic (93), followed by diclofenac (80), metamizole (76), and morphine (76). Parecoxib remained the most preferred analgesic in several other sensitivity analyses. CONCLUSION: This MCDA-based assessment suggests that parecoxib has the most favorable efficacy-safety profile among the assessed postoperative analgesics.

Medical cannabis in the UK: From principle to practice.

BACKGROUND: In the UK, medical cannabis was approved in November 2018, leading many patients to believe that the medicine would now be available on the NHS. Yet, to date, there have been only 12 NHS prescriptions and less than 60 prescriptions in total. In marked contrast, a recent patient survey by the Centre for Medical Cannabis (Couch, 2020) found 1.4 m people are using illicit cannabis for medical problems. AIMS: Such a mismatch between demand and supply is rare in medicine. This article outlines some of the current controversies about medical cannabis that underpin this disparity, beginning by contrasting current medical evidence from research studies with patient-reported outcomes. OUTCOMES: Although definite scientific evidence is scarce for most conditions, there is significant patient demand for access to medical cannabis. This disparity poses a challenge for prescribers, and there are many concerns of physicians when deciding if, and how, to prescribe medical cannabis which still need to be addressed. Potential solutions are outlined as to how the medical profession and regulators could respond to the strong demand from patients and families for access to medical cannabis to treat chronic illnesses when there is often a limited scientific evidence base on whether and how to use it in many of these conditions. CONCLUSIONS: There is a need to maximise both clinical research and patient benefit, in a safe, cautious and ethical manner, so that those patients for whom cannabis is shown to be effective can access it. We hope our discussion and outlines for future progress offer a contribution to this process.

Multicriteria Decision Analysis Applied to the Clinical Use of Pharmacotherapy for Overactive Bladder Symptom Complex.

CONTEXT: The nonspecific storage symptom complex overactive bladder (OAB) is an important clinical condition in functional urology. Until recently, pharmacological therapy comprised antimuscarinic drugs, but more recently beta 3 agonists have added to the available agents. Traditional reporting of efficacy and safety of these agents relies upon regulatory placebo-controlled studies. There remains no head-to-head comparison of existing agents in the contemporary literature. Contemporary conclusions on comparative efficacy and safety drawn from the use of these agents are based on systematic reviews of the literature and associated meta-analyses. OBJECTIVE: In this study, we used the analytical model of multicriteria decision analysis (MCDA) to compare contemporary pharmacotherapy for OAB. EVIDENCE ACQUISITION: Efficacy and safety data from published, randomised, placebo-controlled trials of antimuscarinic antagonists, the beta 3 agonist, and the combination of an antimuscarinic and beta 3 agonist were used to populate the MCDA model. EVIDENCE SYNTHESIS: Experts assessed weights of the relative importance of favourable and unfavourable effects, which provided a common measure of benefits and safety that were combined in the MCDA model to give an overall ranking of the OAB drugs. RESULTS: When benefits are judged as more important than safety, fesoterodine 4 or 8mg used in a flexible dosing pattern provides the most favourable therapeutic option, over a wide sensitivity analysis relating to benefits and harms. CONCLUSIONS: In our analysis using an MCDA model, in both the flexible dosing pattern of fesoterodine and the solifenacin combination with mirabegron, the benefit-safety balance is better in terms of benefits and/or safety than any of the other available OAB drugs. Caution in interpretation of the data has to be expressed as the fesoterodine data are based on a flexible dosing regimen, which adds an additional dimension of personalising therapy. PATIENT SUMMARY: Overactive bladder (OAB) is a common condition with a significant impact on the quality of life. Possible symptoms include the following: (1) urgency-a compelling desire to urinate, which is difficult to defer; (2) urgency urinary incontinence-urgency leading to incontinence episodes; (3) frequency-increased frequency of wanting to pass urine; and (4) nocturia-increase in instances of getting up at night to urinate. To date, the mainstay of therapy for OAB has been antimuscarinic drugs and, more recently, the beta 3 agonist mirabegron. Ten international experts in urology, obstetrics, gynaecology, healthy ageing, and data analysis compared the benefit-risk balance of 14 OAB drugs licensed in Europe. The experts considered the importance of a favourable effect on the above four symptoms and also potential for side effects, but only three of these side effects, constipation, dry mouth, and dizziness, showed clinically relevant differences among the six drugs they considered. The observations recorded here suggest interesting differences between drugs across a wide range of possible trade-offs between benefit and safety. The different recruitment criteria used for each study may influence the results seen, so they need to be treated with caution. Comparison of flexibly dosed fesoterodine studies with fixed-dose fesoterodine studies introduces an additional potential bias; definitive conclusions can be drawn only if enough comparable placebo-controlled flexible dosing studies with other drugs were available.

Quantifying Preferences in Drug Benefit-Risk Decisions.

Benefit-risk assessment is used in various phases along the drug lifecycle, such as marketing authorization and surveillance, health technology assessment (HTA), and clinical decisions, to understand whether, and for which patients, a drug has a favorable or more valuable profile with reference to one or more comparators. Such assessments are inherently preference-based as several clinical and nonclinical outcomes of varying importance might act as evaluation criteria, and decision makers must establish acceptable trade-offs between these outcomes. Different healthcare stakeholder perspectives, such as those from patients and healthcare professionals, are key for informing benefit-risk trade-offs. However, the degree to which such preferences inform the decision is often unclear as formal preference-based evaluation frameworks are generally not used for regulatory decisions, and, if used, rarely communicated in HTA decisions. We argue that for better decisions, as well as for reasons of transparency, preferences in benefit-risk decisions should more often be quantified and communicated explicitly.

Benefit-risk Assessment of Cladribine Using Multi-criteria Decision Analysis (MCDA) for Patients With Relapsing-remitting Multiple Sclerosis.

PURPOSE: We applied Multi-Criteria Decision Analysis (MCDA) methods in a structured benefit-risk assessment of cladribine and newer approved disease-modifying drugs (DMDs) for patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Decision conferencing with clinical neurologists as decision makers was used to create an MCDA model that incorporated available evidence on DMDs for RRMS and clinical judgments about the relevance of the evidence. Benefit-risk assessments were conducted for DMDs in both patients with RRMS and patients with RRMS with high disease activity (HDA; defined as ≥2 relapses in the previous year). Treatment options included cladribine and recently approved DMDs available in European Union countries at the time of assessment (December 2015): alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, and teriflunomide. To account for the relative importance of DMD effects, scores for the MCDA model were weighted to ensure that the most clinically important attributes carried more weight in the final benefit-risk calculation. The neurologists weighted different efficacy and safety profile attributes without any reference to individual DMDs to disassociate the assessment of weights with any specific DMD. The neurologists did not do direct comparisons between DMDs. FINDINGS: The highest overall weighted preference value for the RRMS model was for dimethyl fumarate (63) followed closely by cladribine (62). For patients with RRMS and HDA, cladribine had the highest overall weighted preference value (76), followed by alemtuzumab (62) and natalizumab (61). The benefit-risk balance of cladribine in patients with RRMS and specifically patients with RRMS who exhibited HDA characterized by high relapse activity (≥2 relapses in the previous year) was more favorable than the other DMDs included in the model. IMPLICATIONS: The balance of high efficacy and the safety profile makes cladribine an important treatment option to consider, both in patients with RRMS and patients with HDA. Regular, single-country meetings could be organized to explore how differences in cultural values (scores and weights) and updated input data might affect the usefulness of MCDA in different, real-world, dynamic clinical settings.

10-Year Resource Utilization and Costs for Cardiovascular Care.

BACKGROUND: Cardiovascular disease (CVD) imparts a heavy economic burden on the U.S. health care system. Evidence regarding the long-term costs after comprehensive CVD screening is limited. OBJECTIVES: This study calculated 10-year health care costs for 6,814 asymptomatic participants enrolled in MESA (Multi-Ethnic Study of Atherosclerosis), a registry sponsored by the National Heart, Lung, and Blood Institute, National Institutes of Health. METHODS: Cumulative 10-year costs for CVD medications, office visits, diagnostic procedures, coronary revascularization, and hospitalizations were calculated from detailed follow-up data. Costs were derived by using Medicare nationwide and zip code-specific costs, inflation corrected, discounted at 3% per year, and presented in 2014 U.S. dollars. RESULTS: Risk factor prevalence increased dramatically and, by 10 years, diabetes, hypertension, and dyslipidemia was reported in 19%, 57%, and 53%, respectively. Self-reported symptoms (i.e., chest pain or shortness of breath) were common (approximately 40% of enrollees). At 10 years, approximately one-third of enrollees reported having an echocardiogram or exercise test, whereas 7% underwent invasive coronary angiography. These utilization patterns resulted in 10-year health care costs of $23,142. The largest proportion of costs was associated with CVD medication use (78%). Approximately $2 of every $10 were spent for outpatient visits and diagnostic testing among the elderly, obese, those with a high-sensitivity C-reactive protein level >3 mg/l, or coronary artery calcium score (CACS) ≥400. Costs varied widely from <$7,700 for low-risk (Framingham risk score <6%, 0 CACS, and normal glucose measurements at baseline) to >$35,800 for high-risk (persons with diabetes, Framingham risk score ≥20%, or CACS ≥400) subgroups. Among high-risk enrollees, CVD costs accounted for $74 million of the $155 million consumed by MESA participants. CONCLUSIONS: Longitudinal patterns of health care resource use after screening revealed new evidence on the economic burden of treatment and testing patterns not previously reported. Maintenance of a healthy population has the potential to markedly reduce the economic burden of CVD among asymptomatic individuals.

A new approach to formulating and appraising drug policy: A multi-criterion decision analysis applied to alcohol and cannabis regulation.

BACKGROUND: Drug policy, whether for legal or illegal substances, is a controversial field that encompasses many complex issues. Policies can have effects on a myriad of outcomes and stakeholders differ in the outcomes they consider and value, while relevant knowledge on policy effects is dispersed across multiple research disciplines making integrated judgements difficult. METHODS: Experts on drug harms, addiction, criminology and drug policy were invited to a decision conference to develop a multi-criterion decision analysis (MCDA) model for appraising alternative regulatory regimes. Participants collectively defined regulatory regimes and identified outcome criteria reflecting ethical and normative concerns. For cannabis and alcohol separately, participants evaluated each regulatory regime on each criterion and weighted the criteria to provide summary scores for comparing different regimes. RESULTS: Four generic regulatory regimes were defined: absolute prohibition, decriminalisation, state control and free market. Participants also identified 27 relevant criteria which were organised into seven thematically related clusters. State control was the preferred regime for both alcohol and cannabis. The ranking of the regimes was robust to variations in the criterion-specific weights. CONCLUSION: The MCDA process allowed the participants to deconstruct complex drug policy issues into a set of simpler judgements that led to consensus about the results.

Selecting pH cut-offs for the safe verification of nasogastric feeding tube placement: a decision analytical modelling approach.

OBJECTIVES: The existing British National Patient Safety Agency (NPSA) safety guideline recommends testing the pH of nasogastric (NG) tube aspirates. Feeding is considered safe if a pH of 5.5 or lower has been observed; otherwise chest X-rays are recommended. Our previous research found that at 5.5, the pH test lacks sensitivity towards oesophageal placements, a major risk identified by feeding experts. The aim of this research is to use a decision analytic modelling approach to systematically assess the safety of the pH test under cut-offs 1-9. MATERIALS AND METHODS: We mapped out the care pathway according to the existing safety guideline where the pH test is used as a first-line test, followed by chest x-rays. Decision outcomes were scored on a 0-100 scale in terms of safety. Sensitivities and specificities of the pH test at each cut-off were extracted from our previous research. Aggregating outcome scores and probabilities resulted in weighted scores which enabled an analysis of the relative safety of the checking procedure under various pH cut-offs. RESULTS: The pH test was the safest under cut-off 5 when there was ≥30% of NG tube misplacements. Under cut-off 5, respiratory feeding was excluded; oesophageal feeding was kept to a minimum to balance the need of chest X-rays for patients with a pH higher than 5. Routine chest X-rays were less safe than the pH test while to feed all without safety checks was the most risky. DISCUSSION: The safety of the current checking procedure is sensitive to the choice of pH cut-offs, the impact of feeding delays, the accuracy of the pH in the oesophagus, as well as the extent of tube misplacements. CONCLUSIONS: The pH test with 5 as the cut-off was the safest overall. It is important to understand the local clinical environment so that appropriate choice of pH cut-offs can be made to maximise safety and to minimise the use of chest X-rays. TRIAL REGISTRATION NUMBER: ISRCTN11170249; Pre-results.

Use of multicriteria decision analysis for assessing the benefit and risk of over-the-counter analgesics.

OBJECTIVES: To test the ability of a multicriteria decision analysis (MCDA) model to incorporate disparate data sources of varying quality along with clinical judgement in a benefit-risk assessment of six well-known pain-relief drugs. METHODS: Six over-the-counter (OTC) analgesics were evaluated against three favourable effects and eight unfavourable effects by seven experts who specialise in the relief of pain, two in a 2-day facilitated workshop whose input data and judgements were later peer-reviewed by five additional experts. KEY FINDINGS: Ibuprofen salts and solubilised emerged with the best benefit-risk profile, followed by naproxen, ibuprofen acid, diclofenac, paracetamol and aspirin. CONCLUSIONS: Multicriteria decision analysis enabled participants to evaluate the OTC analgesics against a range of favourable and unfavourable effects in a group setting that enabled all issues to be openly aired and debated. The model was easily communicated and understood by the peer reviewers, so the model should be comprehensible to physicians, pharmacists and other health professionals.

Myocardial perfusion imaging in women for the evaluation of stable ischemic heart disease-state-of-the-evidence and clinical recommendations.

This document from the American Society of Nuclear Cardiology represents an updated consensus statement on the evidence base of stress myocardial perfusion imaging (MPI), emphasizing new developments in single-photon emission tomography (SPECT) and positron emission tomography (PET) in the clinical evaluation of women presenting with symptoms of stable ischemic heart disease (SIHD). The clinical evaluation of symptomatic women is challenging due to their varying clinical presentation, clinical risk factor burden, high degree of comorbidity, and increased risk of major ischemic heart disease events. Evidence is substantial that both SPECT and PET MPI effectively risk stratify women with SIHD. The addition of coronary flow reserve (CFR) with PET improves risk detection, including for women with nonobstructive coronary artery disease and coronary microvascular dysfunction. With the advent of PET with computed tomography (CT), multiparametric imaging approaches may enable integration of MPI and CFR with CT visualization of anatomical atherosclerotic plaque to uniquely identify at-risk women. Radiation dose-reduction strategies, including the use of ultra-low-dose protocols involving stress-only imaging, solid-state detector SPECT, and PET, should be uniformly applied whenever possible to all women undergoing MPI. Appropriate candidate selection for stress MPI and for post-MPI indications for guideline-directed medical therapy and/or invasive coronary angiography are discussed in this statement. The critical need for randomized and comparative trial data in female patients is also emphasized.