A review of cost-effectiveness of varenicline and comparison of cost-effectiveness of treatments for major smoking-related morbidities

Rationale This review aims to examine economic evaluations of varenicline, to compare the reported cost‐effectiveness of varenicline with that of treatments for major smoking‐related diseases and to evaluate the findings for decision making. Methods A literature search was performed to identify published articles in English indexed in MEDLINE and the Cochrane Library (Issue 1, 2009), which includes the Economic Evaluation Database. Additional sources also were searched to identify unpublished varenicline studies, including conference abstracts. The search for varenicline studies was limited from 2006 to October 2009; searches for all other types of studies were limited from 1990 to October 2009. Results The search yielded a total of 20 relevant economic evaluations of varenicline. In addition, 37 reviews of economic evaluations in chronic obstructive pulmonary disease, non‐small cell lung cancer and cardiovascular disease, as well as studies evaluating the impact of economic rewarding were considered in this review. From these identified economic evaluations, the incremental cost‐effectiveness ratios for varenicline ranged from dominance (more effective and cost saving) to €18 582 per quality‐adjusted life‐year (including indirect costs). These estimates appeared substantially lower when compared with incremental cost‐effectiveness ratios reported for secondary prevention of smoking‐related diseases, which in some cases were as high as €66 218 per quality‐adjusted life‐year. Conclusions Varenicline appears to be cost‐effective from the perspective of both health care payers and employers, because of reduced health care consumption and costs. The cost‐effectiveness of varenicline also compares favourably to that of interventions recommended for the treatment and prevention of smoking‐related diseases.     

The development of a national guideline on the management of leg ulcers

This paper describes the development of an evidence-linked clinical guideline for the management of uncomplicated venous leg ulcers. Guidelines are developed to provide recommendations for clinical practice which are based on summaries of good quality research evidence. The aim of the guideline discussed in this article is to direct primary health care practitioners to the most effective method of assessment and treatment of venous leg ulcers and to discourage practices that do not have convincing or sufficient evidence of effectiveness. The three most important steps to the development of a valid clinical guideline are: basing recommendations on the best available evidence; explicit linkage between guideline recommendations and quality of evidence; and the involvement of a multidisciplinary group. The steps are discussed in relation to the development of the guideline alongside an introductory presentation on the role guidelines can play in improving practice. Issues arising from guideline development such as valid ways of obtaining patient input and lack of evidence are also discussed.     

The importance of appropriate prophylaxis for the prevention of venous thromboembolism in at‐risk medical patients

Background: Venous thromboembolism (VTE), which encompasses both deep‐vein thrombosis and pulmonary embolism, is a significant healthcare problem, leading to considerable morbidity, mortality and resource utilisation. Aims: This review discusses the adherence to VTE guideline recommendations and the available clinical evidence on the appropriate type, dose and duration of VTE prophylaxis. Methods: A literature survey was conducted using Pub Med and EMBASE to identify publications related to appropriate thromboprophylaxis in medically ill patients at risk of VTE. Results: Despite evidence from clinical trials and national guidelines, VTE prophylaxis in medically ill patients remains underutilised. The use of unfractionated heparin three‐times‐daily, low‐molecular‐weight heparin once‐daily and fondaparinux once‐daily has demonstrated effectiveness in clinical trials of medically ill patients. However, controversy exists about the use of unfractionated heparin twice‐daily, and fondaparinux has not yet received US Food and Drug Administration approval for VTE prophylaxis in medically ill patients. Conclusion: It is important for clinicians to have an understanding of the evidence‐based literature when selecting an appropriate drug, at the appropriate dose, for the appropriate duration for VTE prophylaxis in medically ill patients. VTE prophylaxis in medically ill patients is cost‐effective, and drugs that are expensive may still be cost‐effective when considering improved efficacy and/or safety. Recently, the underutilisation of VTE prophylaxis has led to the involvement of government and other regulatory agencies in an attempt to increase appropriate VTE prophylaxis in US hospitals and improve the clinical and economic outcomes in medical patients at risk of VTE.     

How Low to Go With Lipid-Lowering Therapies in a Cost-effective and Prudent Manner

The 2013 American College of Cardiology/American Heart Association guideline on the treatment of blood cholesterol was a landmark document guiding health care professionals around the globe on how to administer lipid-lowering therapies. Those guidelines were primarily focused on statin therapy benefit groups. The writing committee found insufficient evidence for specific low-density lipoprotein cholesterol (LDL-C) treatment targets. There have been many important updates in the lipid literature since the publication of that document. Most importantly, clinical trials have provided definitive evidence for the pivotal role of LDL-C in atherogenesis and the improvement in clinical outcomes by means of aggressive LDL-C reduction. Ezetimibe, evolocumab, and alirocumab treatment resulted in substantial reductions in major adverse cardiovascular outcomes. These data encourage a discussion on whether LDL-C targets are warranted in primary and/or secondary prevention, and if so, how low should those targets be. In order to answer such questions, the costs and safety of such therapies, as well as the safety of very low levels of LDL-C need to be addressed. This review discusses the relationship between LDL-C lowering and cardiovascular risk reduction, the efficacy, safety, and cost-effectiveness of high-intensity lipid-lowering therapies, and the recommendations from the most recent lipid guidelines.     

From MARS to MAGIC: The remarkable journey through time and space of the Grading of Recommendations Assessment,Development and Evaluation initiative

For over 30 years, “evidence‐based” clinical guidelines remained entrenched in an oversimplified, design‐based, framework for rating the strength of evidence supporting clinical recommendations. The approach frequently equated the rating of evidence with that of the recommendations themselves. “Grading Recommendations Assessment, Development and Evaluation (GRADE)” has emerged as a proposed antidote to obsolete guideline methodology. GRADE sponsors and collaborators are in the process of attempting to amplify and extend the framework to encompass implementation and adaptation of guidelines, above and beyond the evaluation and rating of clinical research. Alternative schemes and models for such extensions are beginning to appear. This commentary reviews the strengths and weaknesses of GRADE with reference to other recent critiques. It considers the GRADE Working Group's “evidence‐to‐decision” extension of the evidence rating framework, together with proposed alternatives. It identifies pitfalls of the GRADE system's cooptation of relational processes necessary to the interpretation and uptake of recommendations that properly belong to end‐users. It also identifies dangers inherent in blurring important boundaries between clinical and policy applications of guidelines. Finally, it addresses criticisms regarding the lack of a theoretical framework supporting the different facets of the GRADE approach and proposes a social constructivist orientation to clinical guideline development and use. Recommendations are offered to potential guideline developers and users regarding how to draw upon the strengths of the GRADE framework without succumbing to its pitfalls.     

Management of hypertension and stroke prevention: results of the Italian cardiologist survey

Objective:  To provide an overview of current habits, priorities, perceptions and knowledge of cardiologists with regard to hypertension and stroke prevention in outpatient practice. Methods:  A sample of 203 cardiologists operating in outpatient clinics and randomly selected amongst members of the largest Italian Outpatient Cardiologist Association were interviewed by e‐mail, in April–May 2007. Results:  The interviewed cardiologists reported that hypertensive outpatients represent a large percentage of their practice population, in which the clinical priority was blood pressure (BP) reduction. Stroke was identified as the most important event to prevent and it was also perceived as the most preventable hypertension‐related cardiovascular event . A remarkably high rate of achieved BP control was reported, to a degree that it is inconsistent with current epidemiological reports and with the relatively low percentage use of combination therapies declared by cardiologists. Additional risk factors, organ damage, diabetes mellitus and atrial fibrillation were consistently reported in hypertensive patients. Among antihypertensive drug classes, a preference for angiotensin‐converting enzyme inhibitors has been expressed by the majority of physicians; this choice was generally justified by evidence derived from international trials or by the antihypertensive efficacy of this drug class. Conclusions:  The results confirm the presence of weaknesses in the current services for patients with hypertension, even when being managed by cardiologists. Discrepancies between perceptions and reality, or clinical practice and guideline recommendations are also highlighted. An analysis of these aspects may help to identify current areas of potential improvement for stroke prevention in the clinical management of hypertension in cardiology practice.     

Unperceived treatment gaps in acute coronary syndromes

Background: Despite a strong evidence‐base for several therapies recommended in the management of acute coronary syndromes (ACS), many patients do not receive these therapies. The barriers preventing translation of evidence into practice are incompletely understood. The aim of this study was to survey clinicians regarding barriers to implementing recommendations of recently published national clinical guidelines and to determine the extent to which these impact clinical practice. Methods: A survey of clinicians at hospitals included in Australian Collaborative Acute Coronary Syndromes Prospective Audit (ACACIA, n = 3402, PML0051) was conducted, measuring self‐stated knowledge, beliefs and guideline‐concordant behaviours in relation to their care of ACS patients. Correlations between individual respondents’ self‐estimated rates and clinician’s institutional rates of guideline‐concordant behaviours were performed. Results: Most respondents (n = 50/86, 58%) were aware of current guidelines and their scope, achieving 7/10 (Interquartile Range (IQR) = 2) median score on knowledge questions. Belief in benefits and agreement with guideline‐recommended therapy was high. However, none of these factors correlated with increased use of guideline therapies. Apart from clopidogrel (r_s = 0.28, p < 0.01) and early interventional therapy for high‐risk non‐ST elevation myocardial infarction (r_s = 0.31, p < 0.01), there were no significant correlations between individual clinicians’ self‐estimated rates of guideline‐concordant practice and rates recorded in ACACIA data for their respective institution. Conclusion: Beliefs about practice do not match actual practice. False beliefs regarding levels of evidence‐based practice may contribute to inadequate implementation of evidence‐based guidelines. Strategies such as continuous real‐time audit and feedback of information for the delivery of care may help clinicians understand their levels of practice better and improve care.     

Emergency department management of hip fractures: Development of an evidence‐based clinical guideline by literature review and consensus

The Emergency Department at Dandenong Hospital has recently developed an evidence‐based clinical guideline for the emergency department management of hip fractures. This paper will comment on the role of clinical guidelines in the emergency department, discuss the process of the development of evidence‐based guidelines for the care of hip fractures and present the evidence found during the development process. Evidence‐based recommendations for practice are made regarding pulse oximetry and supplemental oxygen, preoperative use of skin traction, thromboembolism prophylaxis, pain management including the use of nerve blocks, pressure area care, the use of indwelling urinary catheters and time to surgical repair.     

Nonpharmacological treatments for musculoskeletal pain

BACKGROUND: Several types of physical therapy are used in the management of painful musculoskeletal disorders. These treatment modalities can be broadly categorized as electrotherapy modalities (e.g., transcutaneous electrical nerve stimulation), acupuncture, thermal modalities (e.g., moist heat, ultrasound), manual therapies (e.g., manipulation or massage), or exercise. Within each of these broad categories significant variations in treatment parameters are possible. OBJECTIVE: To consider the evidence base for each of these main categories of physical therapy in the management of musculoskeletal pain. METHOD: To consider the available evidence related to clinical effectiveness and then to review evidence from basic science studies evaluating potentially therapeutic effects of the various therapies. RESULTS: There seems to be evidence from basic science research to suggest that many of the therapies could have potentially therapeutic effects. However, there appears to be limited high-quality evidence from randomized clinical trials to support the therapeutic effectiveness of several of the therapies. CONCLUSIONS: There is some preliminary evidence to support the use of manual therapies, exercise, and acupuncture in the management of some categories of musculoskeletal pain. Limitations of the existing research base are discussed and recommendations for areas of future research are provided.     

The 2012 AHS/AAN guidelines for prevention of episodic migraine: a summary and comparison with other recent clinical practice guidelines

Background.— Updated guidelines for the preventive treatment of episodic migraine have been issued by the American Headache Society (AHS) and the American Academy of Neurology (AAN). We summarize key 2012 guideline recommendations and changes from previous guidelines. We review the characteristics, methods, consistency, and quality of the AHS/AAN guidelines in comparison with recently issued guidelines from other specialty societies. Methods.— To accomplish this, we reviewed the AHS/AAN guidelines and identified comparable recent guidelines through a systematic MEDLINE search. We extracted key data, and summarized and compared the key recommendations and assessed quality using the Appraisal of Guidelines Research and Evaluation‐II (AGREE‐II) tool. We identified 2 additional recent guidelines for migraine prevention from the Canadian Headache Society and the European Federation of Neurological Societies. All of the guidelines used structured methods to locate evidence and linked recommendations with assessment of the evidence, but they varied in the methods used to derive recommendations from that evidence. Results.— Overall, the 3 guidelines were consistent in their recommendations of treatments for first‐line use. All rated topiramate, divalproex/sodium valproate, propranolol, and metoprolol as having the highest level of evidence. In contrast, recommendations diverged substantially for gabapentin and feverfew. The overall quality of the guidelines ranged from 2 to 6 out of 7 on the AGREE‐II tool. Conclusion.— The AHS/AAN and Canadian guidelines are recommended for use on the basis of the AGREE‐II quality assessment. Recommendations for the future development of clinical practice guidelines in migraine are provided. In particular, efforts should be made to ensure that guidelines are regularly updated and that guideline developers strive to locate and incorporate unpublished clinical trial evidence.     

ISPD Cardiovascular and Metabolic Guidelines in Adult Peritoneal Dialysis Patients Part I – Assessment and Management of Various Cardiovascular Risk Factors

Cardiovascular disease contributes significantly to the adverse clinical outcomes of peritoneal dialysis (PD) patients. Numerous cardiovascular risk factors play important roles in the development of various cardiovascular complications. Of these, loss of residual renal function is regarded as one of the key cardiovascular risk factors and is associated with an increased mortality and cardiovascular death. It is also recognized that PD solutions may incur significant adverse metabolic effects in PD patients. The International Society for Peritoneal Dialysis (ISPD) commissioned a global workgroup in 2012 to formulate a series of recommendations regarding lifestyle modification, assessment and management of various cardiovascular risk factors, as well as management of the various cardiovascular complications including coronary artery disease, heart failure, arrhythmia (specifically atrial fibrillation), cerebrovascular disease, peripheral arterial disease and sudden cardiac death, to be published in 2 guideline documents. This publication forms the first part of the guideline documents and includes recommendations on assessment and management of various cardiovascular risk factors. The documents are intended to serve as a global clinical practice guideline for clinicians who look after PD patients. The ISPD workgroup also identifies areas where evidence is lacking and further research is needed.     

Drug reimbursement policies in Canada--need for improved access to critical therapies

Public drug programs in Canada are increasingly implementing cost management strategies. A multidisciplinary review of these strategies--specifically, the special authorization (SA) process--found that implementation of the SA practice is costly and causes inequity in access, underutilization, and delays in treatment for urgently required therapies, all potentially leading to negative health outcomes. We present potential solutions and a set of recommendations for decision-makers to base reimbursement decisions on the best clinical evidence, eliminate regional variability in access, ensure timely access to urgently required treatments, and monitor the impact of reimbursement policies on health outcomes.     

Leitlinie der Arbeitsgruppe Allergologie der ?GDV �C Provokationstestungen zur Abkl?rung von unerw��nschten Arzneireaktionen an Haut und Schleimh?uten

Nowadays, clinical and evidence based guidelines are considered one of the major efforts to improve patient care in medical practices as well as hospital settings. In the literature, clinical guidelines have been defined as "systematically developed statements to assist practitioner and patient decisions about appropriate healthcare for specific clinical circumstances", which promote both clinically effective standards and cost-effective care. Despite controversial discussion about the clinical impact of guidelines, they may provide workable recommendations that may thus be important for improving the individual patient's care. Adverse drug reactions (drug allergies, drug hypersensitivities) often represent a major hazard for the affected patient, and a definite diagnosis is important for further drug therapies in most cases. In this context, any diagnostic procedure must be preceded by an individual risk-benefit assessment. Drug provocation testing is regarded as the gold standard, but this kind of testing should be performed in accordance with established criteria and, in the vast majority of cases, in a hospital setting. In this paper we present a clinical guideline for drug provocation testing in Austria.     

Evidence-based guidelines in laboratory medicine: principles and methods

BACKGROUND: Guidelines are commonly used tools for supporting medical decisions. Formulating evidence-based recommendations has become a leading principle in guideline development. AIM: This narrative review integrates the most recent methods of evidence-based guideline development and adapts those to the field of laboratory medicine. SUMMARY: We present a 10-step process and a list of criteria for the development of laboratory guidelines. Laboratory guidelines should be outcome oriented, be developed by a multidisciplinary team, and begin with a clear statement of the clinical question(s) that the use of the test(s) is addressing. The clinical questions define the type of study designs that offer the best evidence to answer those questions. Guidelines should be based on the critical appraisal and systematic review of literature and explicitly state the strength of evidence supporting each recommendation. Pragmatic considerations dictate that priority is given to topics with the highest clinical or economic impact. Scientific evidence is necessary but insufficient for recommendations, as considered judgment is required about benefits, harms, costs, and local applicability of recommendations. Formal consensus methods are needed when the evidence base is lacking or controversial. Guidelines should be disseminated widely and their impact monitored regularly. Regular reviewing is needed because the lack of timely updates is a major cause of nonadherence to guidelines. CONCLUSIONS: Guidelines should be developed in a transparent process by a multidisciplinary team, with graded recommendations based on critically appraised scientific studies. Systematic, standardized, and explicit methodology, adapted to laboratory medicine, should be followed when developing recommendations involving the use of laboratory tests.     

Clinical Applications of Neurostimulation: Forty Years Later

With the recent technological advances, neurostimulation has provided new hope for millions of patients with debilitating chronic pain conditions that respond poorly to other therapies. Outcome research demonstrated that patients with failed back surgery syndrome and complex regional pain syndromes benefit significantly from neurostimulation in pain reduction, functional capacity, and quality of life. Increasing clinical evidence supports the use of neurostimulation in post‐herpetic neuralgia, peripheral neuropathy, occipital neuralgia, and other neuropathic pain conditions. Strong clinical evidences indicate that neurostimulation offers less invasive and more effective therapies for many patients with ischemic pain caused by cardiovascular and peripheral vascular diseases. A growing body of literature supports neurostimulation for visceral pain in general and interstitial cystitis in particular. As a basic principle, patient selection for the appropriate neurostimulation modalities is essential for safe, efficacious, and cost‐effective applications of this therapy. Research with more vigorous designs is needed to establish evidence‐based applications of neuromodulation therapy in emerging indications of pain management.     

The impact of critical care pharmacists on enhancing patient outcomes

The highly specialized knowledge and skills needed to care for critically ill patients requires a multidisciplinary team approach. Pharmacists are integral members of this team. They make valuable contributions to improve clinical, economic, and humanistic outcomes of patients. The purpose of this article is to review the literature pertaining to pharmacists' contributions within a multidisciplinary intensivist-led intensive care unit (ICU) team. Pharmacist interventions include correcting/clarifying orders, providing drug information, suggesting alternative therapies, identifying drug interactions, and therapeutic drug monitoring. Pharmacist involvement in improving clinical outcomes of critically ill patients is associated with optimal fluid management and substantial reductions in the rates of adverse drug events, medication administration errors, and ventilator-associated pneumonia. Furthermore, economic evaluations of clinical pharmacy services in the ICU consistently reveal the potential for considerable cost savings.     

Going from evidence to recommendations: Can GRADE get us there?

The evidence based medicine movement has championed the need for objective and transparent methods of clinical guideline development. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) framework was developed for that purpose. Central to this framework is criteria for assessing the quality of evidence from clinical studies and the impact that body of evidence should have on our confidence in the clinical effectiveness of a therapy under examination. Grades of Recommendation, Assessment, Development, and Evaluation has been adopted by a number of professional medical societies and organizations as a means for orienting the development of clinical guidelines. As a result, the method of GRADE has implications on how health care is delivered and patient outcomes. In this paper, we reveal several issues with the underlying logic of GRADE that warrant further discussion. First, the definitions of the “grades of evidence” provided by GRADE, while explicit, are functionally vague. Second, the “criteria for assigning grade of evidence” is seemingly arbitrary and arguably logically incoherent. Finally, the GRADE method is unclear on how to integrate evidence grades with other important factors, such as patient preferences, and trade‐offs between costs, benefits, and harms when proposing a clinical practice recommendation. Much of the GRADE method requires judgement on the part of the user, making it unclear as to how the framework reduces bias in recommendations or makes them more transparent—both goals of the programme. It is our view that the issues presented in this paper undermine GRADE's justificatory scheme, thereby limiting the usefulness of GRADE as a tool for developing clinical recommendations.     

European Pain Federation (EFIC) position paper on appropriate use of cannabis‐based medicines and medical cannabis for chronic pain management

Cannabis‐based medicines are being approved for pain management in an increasing number of European countries. There are uncertainties and controversies on the role and appropriate use of cannabis‐based medicines for the management of chronic pain. EFIC convened a European group of experts, drawn from a diverse range of basic science and relevant clinical disciplines, to prepare a position paper to empower and inform specialist and nonspecialist prescribers on appropriate use of cannabis‐based medicines for chronic pain. The expert panel reviewed the available literature and harnessed the clinical experience to produce these series of recommendations. Therapy with cannabis‐based medicines should only be considered by experienced clinicians as part of a multidisciplinary treatment and preferably as adjunctive medication if guideline‐recommended first‐ and second‐line therapies have not provided sufficient efficacy or tolerability. The quantity and quality of evidence are such that cannabis‐based medicines may be reasonably considered for chronic neuropathic pain. For all other chronic pain conditions (cancer, non‐neuropathic noncancer pain), the use of cannabis‐based medicines should be regarded as an individual therapeutic trial. Realistic goals of therapy have to be defined. All patients must be kept under close clinical surveillance. As with any other medical therapy, if the treatment fails to reach the predefined goals and/or the patient is additionally burdened by an unacceptable level of adverse effects and/or there are signs of abuse and misuse of the drug by the patient, therapy with cannabis‐based medicines should be terminated.

Significance

This position paper provides expert recommendations for nonspecialist and specialist healthcare professionals in Europe, on the importance and the appropriate use of cannabis‐based medicines as part of a multidisciplinary approach to pain management, in properly selected and supervised patients.     

A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact

Purpose

This systematic review aimed to assess the literature for management strategies and economic impact of salivary gland hypofunction and xerostomia induced by cancer therapies and to determine the quality of evidence-based management recommendations.

Methods

The electronic databases of MEDLINE/PubMed and EMBASE were searched for articles published in English since the 1989 NIH Development Consensus Conference on the Oral Complications of Cancer Therapies until 2008 inclusive. For each article, two independent reviewers extracted information regarding study design, study population, interventions, outcome measures, results, and conclusions.

Results

Seventy-two interventional studies met the inclusion criteria. In addition, 49 intensity-modulated radiation therapy (IMRT) studies were included as a management strategy aiming for less salivary gland damage. Management guideline recommendations were drawn up for IMRT, amifostine, muscarinic agonist stimulation, oral mucosal lubricants, acupuncture, and submandibular gland transfer.

Conclusions

There is evidence that salivary gland hypofunction and xerostomia induced by cancer therapies can be prevented or symptoms be minimized to some degree, depending on the type of cancer treatment. Management guideline recommendations are provided for IMRT, amifostine, muscarinic agonist stimulation, oral mucosal lubricants, acupuncture, and submandibular gland transfer. Fields of sparse literature identified included effects of gustatory and masticatory stimulation, specific oral mucosal lubricant formulas, submandibular gland transfer, acupuncture, hyperbaric oxygen treatment, management strategies in pediatric cancer populations, and the economic consequences of salivary gland hypofunction and xerostomia.     

Broadening the perspective when assessing evidence on boosted protease inhibitor-based regimens for initial antiretroviral therapy

Several national and international guidelines recommend the use of antiretroviral therapy containing a protease inhibitor (PI) with ritonavir (RTV) boosting for human immunodeficiency virus (HIV)-infected treatment-naïve patients. RTV-boosted PIs such as lopinavir (LPV/r), atazanavir (ATV + RTV), darunavir (DRV + RTV), fosamprenavir (FPV + RTV), and saquinavir (SQV + RTV) are usually recommended in regimens for initial therapy. The guideline recommendations are generally based on the clinical efficacy of the regimens. A broadened perspective of assessing the evidence related to selection of a PI for optimal first-line therapy might consider additional factors for evaluation, such as effectiveness in actual clinical practice and costeffectiveness of individual drugs in formulating recommendations. Among the guidelinerecommended PIs, LPV/r is one of the earliest PIs approved, has been a well-recognized boosted PI for treatment-naïve patients in all guidelines, and demonstrates the most evidence on long-term clinical and economic effectiveness. Studies have shown its efficacy in various controlled and real-world settings in different populations, the relationship of adherence to virologic efficacy, and the implications of resistance when used in sequence with other PI regimens. In the absence of published evidence for other guideline-recommended PIs that will greatly facilitate a fully transparent, comparative effectiveness evaluation, the cumulative evidence from this broader perspective indicates all PIs should not be viewed as equally safe and effective across all patients for initial therapy, nor should any single PI within the class be considered preferred for all treatment-naïve patients.