Professor Brian Andrews NEJM Recommendations
for Medical Students and Tutors
Week of 26th May 2016 (#44)
University of Notre Dame Australia (Fremantle
Campus)
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Must Read Articles
Perspective
Considering
the Common Good — The View from Seven Miles Up
One
patient on the flight from LA to France could benefit from picking up more
oxygen in Chicago; the other might well be harmed by an additional landing and
takeoff. This unusual situation crystallized a common dilemma in medicine.
Whose needs should take precedence?
I found this an excellent perspective which merits deep
reflection. Much too often as physicians we regard patient autonomy
(“individual good”) as the guiding principle in patient care without seriously
considering the “collective good.” This perspective provides an excellent
example whereby a balance is achieved between autonomy and, “respect for the
commons.”
Now in medical practice we need to consider whether the
cost of a newer expensive therapy is justified for the individual (unless of
course the patient can pay for it out of pocket or be included in a clinical
trial) particularly if the outcomes are suboptimal or palliative or if this is
secondary prevention for disease that is eminently preventable in many (obesity
and type II DM). There is a limitation on the size of the public purse and
decisions will be increasingly made with the needs of the entire community
being considered e.g. maintaining Medicare in its current form. Regardless,
compromise will frequently be necessary and needs to be actively considered concerning
the individual patient.
Recommended
learning: Review the ethical principles of autonomy, contrasting
this with the concept of “collective good.”
CLINICAL PRACTICE
Cryptogenic
Stroke
One
quarter of ischemic strokes are cryptogenic (no obvious cause). Additional
investigation involves assessment for arteriopathies, cardiac sources of
embolism (in particular, occult low-burden atrial fibrillation), and
disturbances of coagulation.
This is an excellent review article on cryptogenic
ischaemic strokes which account for 10-40% of all ischaemic strokes. It is
timely, considering the recommendation for early use of recombinant tPA and the
persistent reluctance of many physicians to still regard this as a questionable
therapy, even in appropriate patients.
This article summarises a clinical problem and, after
discussion of many areas, provides guidelines to the management of the
condition.
It provides an excellent overview of the epidemiology
and pathology of ischaemic strokes and reviews the evidence for particular
investigations and treatment strategies.
This review covers in depth the areas of occult atrial
fibrillation, patent foramen ovale and embolic stroke of undetermined source.
Recommended
learning: Review ischaemic strokes, pathology, investigation and
management.
Articles Recommended for Medical Students
IMAGES IN CLINICAL MEDICINE
Acute
Varicocele Revealing Renal Cancer
A
65-year-old man presented to the urology clinic with swelling in the area of
the left testicle that had started 4 weeks earlier. Examination of the scrotum
revealed an enlarged varicose vein along the left spermatic cord, and abdominal
palpation revealed a mass in the right flank.
This is an excellent clinical example of an acute left
sided non-traumatic varicocele due to a left sided renal carcinoma (review CT)
extending into the renal vein and obstructing the left spermatic vein.
Recommended
learning: Review renal tumours and the anatomy and pathology of
the contents of the scrotal sac, in particular the anatomy of the spermatic
veins.
IMAGES IN CLINICAL MEDICINE
Salmonella
enterica Aortitis
A
66-year-old man presented with a 1-month history of fever and 4 days of hoarseness.
His temperature was 38.7°C. The peripheral-blood leukocyte count was elevated,
and a chest radiograph showed enlargement of the aortic arch, with deviation of
the trachea to the right side.
Primary infection of atherosclerotic ulcers by
salmonella species is not uncommon in sub-Saharan Africa as a cause for FUO
where it is usually misdiagnosed as falciparum malaria. In this Japanese
patient, however, a thoracic aortic aneurysm was infected and ultimately
resulted in the patient’s demise despite optimal treatment. Very interesting
CXR and thoracic CTs are illustrated.
CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL
Case
16-2016 — A 31-Year-Old Pregnant Woman with Fever
A
31-year-old woman who was pregnant with dichorionic, diamniotic twins presented
at 35 weeks of gestation with fever, rigor, malaise, myalgias, anorexia, and loose
stools. A chest radiograph revealed patchy right basilar opacities. Diagnostic
test results were received.
All students should read this CPC, particularly the
discussion of the differential diagnosis of fever during pregnancy. This is a
31 year old patient with twins who developed systemic symptoms and fever at 35
weeks gestation and who was subsequently diagnosed with chorioamnionitis. Don’t
look up the cause before reading the DD
.
Recommended
learning: Causes and management of fever during various stages
of pregnancy.
Important Articles Related to Mechanisms of Disease and
Translational Research
CLINICAL IMPLICATIONS OF BASIC RESEARCH
Repressing
Immunity in Autoimmune Disease
Great
strides have been made in new strategies to treat cancer by derepressing
effector T cells. Repressing exuberant immunity to treat autoimmune disease has
not had the same level of success in the clinic. A recent study of mouse models
shows a potential strategy.
There are two types of peripheral regulatory T
lymphocytes. The first identified was the CD4+, CD25+ FOXP3+ cell which
suppresses or down-regulates induction and proliferation of effector T cells.
The second type is the type 1 regulatory T (Tr1) cell which is derived from Th1
cells under the influence of IL-10 and IFN-g.
This cell controls specific antigen presenting cells and effector T cells by
anti-inflammatory cytokines (IL-10, IL-21 and TGF-b) and by secondary reactivation of specific regulatory
B cells (see Figure 1).
To date, the use of regulatory T cells in the treatment
of autoimmune and inflammatory diseases have produced cells with various
antigen specificities with limited effectiveness.
A recent study by Clemente-Casares,
Santamaria et al in Nature, 2016 described mice with type
1 diabetes mellitus, experimental autoimmune encephalitis, and collagen-induced
arthritis that were treated with disease-specific antigenic peptide in the
context of MHC II bound to nanoparticles (pMHCII-NPs). This antigen specific
therapy resulted in clinical improvement in these murine autoimmune diseases
(Figure 1). This therapy is not ready for clinical testing but areas such as
generalized immunosuppression and durability of the protective immune response need
to be further explored. This novel approach offers an insight into future treatments
of autoimmune disorders.
Other Articles which should interest medical students
ORIGINAL ARTICLE
Blood-Pressure
Lowering in Intermediate-Risk Persons without Cardiovascular Disease
In
one comparison from a 2-by-2 factorial trial, over 12,000 participants with a
mean baseline blood pressure of 138/82 mm Hg were assigned to candesartan plus
hydrochlorothiazide or to placebo. At 5.6 years, there was no between-group
difference in the rates of cardiovascular events.
ORIGINAL ARTICLE
Cholesterol
Lowering in Intermediate-Risk Persons without Cardiovascular Disease
In
one comparison from a 2-by-2 factorial trial, 12,705 persons at intermediate
cardiovascular risk were assigned to either rosuvastatin or placebo. At 5.6
years, there were significantly fewer participants with cardiovascular events
in the rosuvastatin group than in the placebo group.
ORIGINAL ARTICLE
Blood-Pressure
and Cholesterol Lowering in Persons without Cardiovascular Disease
In
a 2-by-2 factorial trial, 12,705 persons at intermediate risk were assigned to
candesartan plus hydrochlorothiazide or placebo and to rosuvastatin or placebo.
At 5.6 years, combination therapy resulted in a significantly lower risk of
cardiovascular events than dual placebo.
EDITORIAL
More
HOPE for Prevention with Statin
The above three articles and the accompanying editorial
relate to the HOPE-3 study (Heart Outcomes Prevention Evaluation) which is a
large (12,705 patients, randomized, double-blinded, placebo-control, international
and using 228 centres in 21 countries) study with McMaster University
coordinating the entire data base and data analysis.
To me the data demonstrate that for patients without
clinically apparent cardiovascular disease who are judged to be at intermediate
risk for a cardiovascular event:
1. Treatment
of systolic BP levels (fixed dose candesartan 16 mg/day with
hydrochlorothiazide 12.5 mg/day) greater than 140 mm Hg (in study >143.5 mm
Hg) result in a decrease in cardiovascular events over the 5.6 year study (http://www.nejm.org/doi/full/10.1056/NEJMoa1600175)
(Forest plots in Figure 3). The summary is a little disingenuous in that the
summary states that lowering of systolic BP in intermediate risk patients
(130-160 mm Hg) did not reduce the risk of cardiovascular events, although
clearly treatment of BP at levels of > 140 mm Hg did.
2. Treatment
with statins (fixed dose of rosuvastatin 10 mg/day) resulted in decreased
cardiovascular events, and
3. The
combined use of a statin and dual antihypertensive therapy resulted in a
significantly lower risk of cardiovascular events without addition of
significant side effects.
There are several caveats to this study:
1. A
fixed dosage of drugs is used so results can be interpreted only for these drugs
and doses.
2. The
definition of “intermediate risk of cardiovascular event” is found either in
“trial population” or “eligibility” in the papers of the same patient
population. The devil is in the detail.
3. The
relatively short length of the study (5.6 years) is problematic.
Further analyses of the data and a discussion of the
SPRINT trial (see review #18) can be found in the accompanying editorial.
ORIGINAL ARTICLE
Factor
VIII–Mimetic Function of Humanized Bispecific Antibody in Hemophilia A
Emicizumab
is a humanized bispecific antibody that mimics the cofactor function of factor
VIII. In a dose-escalation study in Japanese persons with hemophilia A,
including those with factor VIII inhibitors, emicizumab markedly reduced the
number of bleeding episodes.
ORIGINAL ARTICLE
A
Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A
In
a randomized, multicenter trial involving boys with severe hemophilia A, the
incidence of neutralizing antibodies to factor VIII was 87% higher with
recombinant factor VIII products than with plasma-derived factor VIII products.
EDITORIAL
Hemophilia
Therapy — Navigating Speed Bumps on the Innovation Highway
Both of the above studies and the accompanying
editorial relate to advances in management of severe haemophilia A (factor VIII
coagulant activity < 1 IU/dl).
The first study employs emicizumab, a humanized
monoclonal antibody which binds to two epitopes (bispecific), which are
situated on activated factor IX and factor X. The bridging of these two
clotting factors emulates the action of factor VIII and this binding is not
affected by IgG4 inhibitory anti factor VIII antibodies (factor VIII
inhibitors). The results of this open-label, nonrandomized trial in 18 Japanese
patients using varying doses of subcutaneous weekly emicizumab showed that the
drug markedly reduced the bleeding rate in this patient group with or without
the presence of factor VIII inhibitors.
The second important study relates to patients treated de novo with either recombinant factor
VIII or plasma-derived factor VIII containing von Willebrand factor. This is a
randomized trial with data on 251 patients (see criteria for inclusion). While
both therapies resulted in formation of factor VIII inhibitors, those treated
with plasma-derived factor VIII with von Willebrand factor had a significantly
lower frequency of inhibitors. The reason for the higher frequency of
inhibitors in patients treated with recombinant factor VIII may relate to
glycosylation of the factor VIII and lack of association with von Willebrand
factor in the preparation.
The long-term future of haemophilia (A and B)
management and other single protein deficiency states will be by gene
replacement, which has been achieved in humans with factor IX deficiency using
an adenovirus vector (AVV9) containing the factor IX gene. (NEJM,
November 20, 2014). Genetic
transfer studies were recently reviewed (#36,
search blog).
