treatment

Aortic valve replacement versus conservative treatment in asymptomatic severe aortic stenosis: long-term follow-up of the AVATAR trial

Author/s: 
Marko Banovic, Svetozar Putnik, Bruno R Da Costa, Martin Penicka, Marek A Deja, Martin Kotrc

Background and aims: The question of when and how to treat truly asymptomatic patients with severe aortic stenosis (AS) and normal left ventricular (LV) systolic function is still subject to debate and ongoing research. Here, the results of extended follow-up of the AVATAR trial are reported (NCT02436655, clinical trials.gov).

Methods: The AVATAR trial randomly assigned patients with severe, asymptomatic AS and LV ejection fraction ≥50% to undergo either early surgical aortic valve replacement (AVR) or conservative treatment with watchful waiting strategy. All patients had negative exercise stress testing. The primary hypothesis was that early AVR will reduce a primary composite endpoint comprising all-cause death, acute myocardial infarction, stroke or unplanned hospitalization for heart failure (HF), as compared to conservative treatment strategy.

Results: A total of 157 low-risk patients (mean age 67 years, 57% men, mean Society of Thoracic Surgeons score 1.7%) were randomly allocated to either early AVR group (n=78) or conservative treatment group (n=79). In an intention-to-treat analysis, after a median follow-up of 63 months, the primary composite endpoint outcome event occurred in 18/78 patients (23.1%) in the early surgery group and in 37/79 patients (46.8%) in the conservative treatment group (hazard ratio [HR] early surgery vs. conservative treatment 0.42; 95% confidence interval [CI] 0.24-0.73, p=0.002). The Kaplan-Meier estimates for individual endpoints of all-cause death and HF hospitalization were significantly lower in the early surgery compared with the conservative group (HR 0.44; 95% CI 0.23-0.85, p=0.012 for all-cause death, and HR 0.21; 95% CI 0.06-0.73, p=0.007 for HF hospitalizations).

Conclusions: The extended follow-up of the AVATAR trial demonstrates better clinical outcomes with early surgical AVR in truly asymptomatic patients with severe AS and normal LV ejection fraction compared with patients treated with conservative management on watchful waiting.

Diagnosis and management of patients with polyneuropathy

Author/s: 
Mirian, A., Aljohani, Z., Grushka, D., Florendo-Cumbermack, A.

Polyneuropathy is a common neurologic condition with an overall prevalence in the general population of about 1%–3%, increasing to roughly 7% among people older than 65 years. Polyneuropathy has many causes, and can present in many different ways; thus, it requires a logical clinical approach for evaluation, diagnosis and management. We review the approach to evaluating a patient with polyneuropathy by highlighting important aspects of the history and neurologic examination. We focus on the role of diagnostic investigations for distal symmetric polyneuropathy (DSP), the most common subtype, and an approach to the symptomatic treatment of painful diabetic polyneuropathy (PDN). We draw on practice based guidelines, meta-analyses and systematic reviews, where
possible, as they represent the highest levels of evidence (Box 1).

Neutropenia

Author/s: 
Mithoowani, Siraj, Cameron, L., Crowther, M. A.

»Neutropenia is seen in 5%–10% of healthy people
Based on absolute neutrophil count, neutropenia is commonly defined as
mild (1.0–1.5 × 109
/L), moderate (0.5–0.9 × 109
/L) or severe (< 0.5 × 109
/L).1
However, the reference interval is specific to the population. Mild asymptomatic neutropenia per the above definition is common in people of subSaharan African, Arab or West Indian ancestry,2
and is strongly associated
with the Duffy-null phenotype of red blood cells that protects against
Plasmodium vivax malaria.
2 Common causes include medications, infection, nutritional
deficiency, malignant disease and autoimmune disease
Causes include underproduction (e.g., myelodysplastic syndrome),
immune-mediated destruction or redistribution of neutrophils to the
endothelium and reticuloendothelial system. Antithyroid, anti-infective
and psychotropic drugs, as well as chemotherapy, are causes of druginduced neutropenia.3,4 Transient neutropenia may occur after acute
viral infection and typically resolves within 2 weeks. Joint swelling, rash,
bony pain, splenomegaly or lymphadenopathy may suggest malignant or
autoimmune disease.
3Investigation should begin with a repeat complete blood count
and peripheral blood film
Neutropenia is often identified incidentally. Persistent and unexplained
neutropenia requires further work-up for a range of causes, including
chronic viral infection (e.g., hepatitis, HIV) and nutritional deficiency (e.g.,
vitamin B12) (Appendix 1, available at www.cmaj.ca/lookup/doi/10.1503/
cmaj.220499/tab-related-content).
4 Treatment of mild neutropenia should be directed at the
underlying cause
Patients with mild neutropenia are not at substantially increased risk of
infection.5
The neutrophil count should be checked every 3–6 months for
at least 1 year to rule out progression to more severe neutropenia.
5 Patients with moderate-to-severe neutropenia for more than
6 months should be referred to a specialist
Patients with recurrent or severe bacterial infections (e.g., requiring hospital admission or intravenous antibiotics), abnormalities on peripheral blood
films (e.g., circulating blasts, hairy cells, large granular lymphocytes, dysplastic granulocytes) or pancytopenia also warrant referral to a specialist
(e.g., hematologist, internist, pediatrician).1
Febrile neutropenia (absolute
neutrophil count < 0.5 × 109
/L and an oral temperature > 38.0°C sustained
over 1 h) requires immediate treatment with broad-spectrum antibiotics.

Migraine — Treatment and Preventive Therapies

Author/s: 
Armand, C.E., Loder, E., Ropper, A. H.

In this instructional video, Drs. Cynthia Armand and Elizabeth Loder discuss the clinical presentation and pathophysiology of migraine and treatment options for patients.

This video provides essential and useful information for any clinician caring for patients with this common condition. Newer acute and preventive therapies — including triptans, gepants, ditans, and injectable monoclonal antibodies — are discussed, as are the importance of a patient-centered approach and the need to tackle challenges of access to these newer agents.

Chronic anal pain: A review of causes, diagnosis, and treatment

Author/s: 
Knowles, C. H., Cohen, R. C.

Chronic anal pain is diffi cult to diagnose and treat, especially with no obvious anorectal cause apparent on clinical examination. This review identifi es 3 main diagnostic
categories for chronic anal pain: local causes, functional
anorectal pain, and neuropathic pain syndromes. Conditions covered within these categories include proctalgia
fugax, levator ani syndrome, pudendal neuralgia, and coccygodynia. The signs, symptoms, relevant diagnostic tests,
and main treatments for each condition are reviewed.

Comparison of Amitriptyline and US Food and Drug Administration–Approved Treatments for Fibromyalgia A Systematic Review and Network Meta-analysis

Author/s: 
Farag, H. M., Yunusa, I., Goswami, H., Sultan, I., Doucette, J. A., Eguale, T.

Importance: Amitriptyline is an established medication used off-label for the treatment of fibromyalgia, but pregabalin, duloxetine, and milnacipran are the only pharmacological agents approved by the US Food and Drug Administration (FDA) to treat fibromyalgia.

Objective: To investigate the comparative effectiveness and acceptability associated with pharmacological treatment options for fibromyalgia.

Data sources: Searches of PubMed/MEDLINE, Cochrane Library, Embase, and Clinicaltrials.gov were conducted on November 20, 2018, and updated on July 29, 2020.

Study selection: Randomized clinical trials (RCTs) comparing amitriptyline or any FDA-approved doses of investigated drugs.

Data extraction and synthesis: This study follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. Four independent reviewers extracted data using a standardized data extraction sheet and assessed quality of RCTs. A random-effects bayesian network meta-analysis (NMA) was conducted. Data were analyzed from August 2020 to January 2021.

Main outcomes and measures: Comparative effectiveness and acceptability (defined as discontinuation of treatment owing to adverse drug reactions) associated with amitriptyline (off-label), pregabalin, duloxetine, and milnacipran (on-label) in reducing fibromyalgia symptoms. The following doses were compared: 60-mg and 120-mg duloxetine; 150-mg, 300-mg, 450-mg, and 600-mg pregabalin; 100-mg and 200-mg milnacipran; and amitriptyline. Effect sizes are reported as standardized mean differences (SMDs) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes with 95% credible intervals (95% CrIs). Findings were considered statistically significant when the 95% CrI did not include the null value (0 for SMD and 1 for OR). Relative treatment ranking using the surface under the cumulative ranking curve (SUCRA) was also evaluated.

Results: A total of 36 studies (11 930 patients) were included. The mean (SD) age of patients was 48.4 (10.4) years, and 11 261 patients (94.4%) were women. Compared with placebo, amitriptyline was associated with reduced sleep disturbances (SMD, -0.97; 95% CrI, -1.10 to -0.83), fatigue (SMD, -0.64; 95% CrI, -0.75 to -0.53), and improved quality of life (SMD, -0.80; 95% CrI, -0.94 to -0.65). Duloxetine 120 mg was associated with the highest improvement in pain (SMD, -0.33; 95% CrI, -0.36 to -0.30) and depression (SMD, -0.25; 95% CrI, -0.32 to -0.17) vs placebo. All treatments were associated with inferior acceptability (higher dropout rate) than placebo, except amitriptyline (OR, 0.78; 95% CrI, 0.31 to 1.66). According to the SUCRA-based relative ranking of treatments, duloxetine 120 mg was associated with higher efficacy for treating pain and depression, while amitriptyline was associated with higher efficacy for improving sleep, fatigue, and overall quality of life.

Conclusions and relevance: These findings suggest that clinicians should consider how treatments could be tailored to individual symptoms, weighing the benefits and acceptability, when prescribing medications to patients with fibromyalgia.

Nonspecific Low Back Pain

Author/s: 
Chiarotto, A., Koes, B. W.

Low back pain typically defined as pain below the costal margin and above the inferior gluteal folds with or without leg pain 1 is worldwide the most prevalent and most disabling of the conditions that are considered to benefit from rehabilitation 2 In a systematic review that included 165 studies from 54 countries the mean point prevalence of low back pain in the general adult population was approximately 12 with a higher prevalence among persons 40 years of age or older and among women the lifetime prevalence was approximately 40 3 Low back pain is classified as specific pain and other symptoms that are caused by specific pathophysiological mechanisms of nonspinal or spinal origin or nonspecific back pain with or without leg pain without a clear nociceptive-specific cause 4 Nonspinal causes of specific low back pain include hip conditions diseases of the pelvic organs e g prostatitis and endometriosis and vascular e g aortic aneurysm or systemic disorders spinal causes include herniated disk spinal stenosis fracture tumor infection and axial spondyloarthritis Lumbar disorders with radicular pain due to nerve-root involvement have a higher prevalence 5 to 10 than other spinal causes the two most frequent causes of such back pain are herniated disk and spinal stenosis 5 The overall prevalence of the other spinal disorders is low among patients with acute low back pain For example among 1172 patients who presented to primary care clinicians in Australia with acute low back pain only 11 0 9 were found to have serious spinal conditions mostly fractures during 1 year of follow-up 6 The authors of a Dutch study that involved primary care patients reported axial spondyloarthritis in almost one quarter of adults 20 to 45 years of age who presented with chronic low back pain 7 although these findings have not been replicated In contrast to low back pain caused by specific identifiable causes nonspecific low back pain probably develops from the interaction of biologic psychological and social factors 4 and it accounts for approximately 80 to 90 of all cases of low back pain 1 Low back pain is usually classified according to pain duration as acute 6 weeks subacute 6 to 12 weeks or chronic 12 weeks

Oral Antiviral Medications for COVID-19

Author/s: 
Petty, L. A., Malani, P. N.

Twonewantiviralmedications, ritonavir-boostednirmatrelvir (Paxlovid,
ie, nirmatrelvir-ritonavir) and molnupiravir (Lagevrio), are currently
available in theUS underemergency useauthorization. These 2 drugs
areauthorized for treatmentofpatientswithmild tomoderateCOVID19 who are not currently hospitalized but are at high risk of developingseveredisease.Nirmatrelvir-ritonavirandmolnupiravirareapproved
for use only within 5 days of onset of COVID-19 symptoms.
Nirmatrelvir-ritonavir andmolnupiravir should be considered for
patients with symptoms of COVID-19 who test positive for SARSCoV-2 and either are an older adult (aged 65 years or older) or are
aged 12 years or older with an underlying condition that increases
risk of severe outcomes of COVID-19 (such as cancer, heart disease,
diabetes, and obesity).

Diagnosis and Treatment of Pulmonary Arterial Hypertension: A Review

Author/s: 
Ruopp, N. F., Cockrill, B. A.

Importance: Pulmonary arterial hypertension (PAH) is a subtype of pulmonary hypertension (PH), characterized by pulmonary arterial remodeling. The prevalence of PAH is approximately 10.6 cases per 1 million adults in the US. Untreated, PAH progresses to right heart failure and death.

Observations: Pulmonary hypertension is defined by a mean pulmonary artery pressure greater than 20 mm Hg and is classified into 5 clinical groups based on etiology, pathophysiology, and treatment. Pulmonary arterial hypertension is 1 of the 5 groups of PH and is hemodynamically defined by right heart catheterization demonstrating a mean pulmonary artery pressure greater than 20 mm Hg, a pulmonary artery wedge pressure of 15 mm Hg or lower, and a pulmonary vascular resistance of 3 Wood units or greater. Pulmonary arterial hypertension is further divided into subgroups based on underlying etiology, consisting of idiopathic PAH, heritable PAH, drug- and toxin-associated PAH, pulmonary veno-occlusive disease, PAH in long-term responders to calcium channel blockers, and persistent PH of the newborn, as well as PAH associated with other medical conditions including connective tissue disease, HIV, and congenital heart disease. Early presenting symptoms are nonspecific and typically consist of dyspnea on exertion and fatigue. Currently approved therapy for PAH consists of drugs that enhance the nitric oxide-cyclic guanosine monophosphate biological pathway (sildenafil, tadalafil, or riociguat), prostacyclin pathway agonists (epoprostenol or treprostinil), and endothelin pathway antagonists (bosentan and ambrisentan). With these PAH-specific therapies, 5-year survival has improved from 34% in 1991 to more than 60% in 2015. Current treatment consists of combination drug therapy that targets more than 1 biological pathway, such as the nitric oxide-cyclic guanosine monophosphate and endothelin pathways (eg, ambrisentan and tadalafil), and has shown demonstrable improvement in morbidity and mortality compared with the previous conventional single-pathway targeted monotherapy.

Conclusions and relevance: Pulmonary arterial hypertension affects an estimated 10.6 per 1 million adults in the US and, without treatment, typically progresses to right heart failure and death. First-line therapy with drug combinations that target multiple biological pathways are associated with improved survival.

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