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RxFiles:Objective Comparative
Drug Information Trial
Summaries |
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QUICK LINKS → |
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Trial |
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(2019) |
Dapagliflozin
neither increased nor decreased the risk of MACE, as it remained neutral
compared to placebo. Ongoing investigation of dapagliflozin’s
potential role in HHF reduction is underway in the DAPA-HF trial (see
“uncertainties” section for more on HHF). Presently within the SGLT-2
inhibitor class, the results of the EMPA-REG and CANVAS trials seem to be
more compelling showing empagliflozin and canagliflozin’s CV benefits. The DAPA-CKD trial is
currently attempting to determine the possibility of dapagliflozin
therapy leading to renal benefits in CKD patients. |
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(2019) |
Canagliflozin
may be considered 2 nd line for patients with long
standing T2DM and high risk of renal complications (i.e. Stage 2 or 3 CKD
with nephropathy) to provide renal and cardiovascular protection in addition
to using renoprotective medications (i.e. RAAS
inhibitors). The renoprotective benefit should be
weighed against the potential harms; amputation concerns CANVAS, genital
infections, Fournier’ gangrene and acute kidney injury. There is also limited
long term safety data. Renal benefit was realized despite A1C not at target
(mean A1C reduction of 0.25%; baseline A1C=8.3%) as well as modest decreases
in weight and blood pressure. |
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(2010) |
A synopsis
of the purposes, parameters, and outcome evidence for the following trials:
DCCT, DCCT/EDIC, UKPDS-33, UKPDS-34, |
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Prevention Trials Summary (2008) |
An overview of the following drug trials, which focused on the
efficacy in preventing the onset of Diabetes Mellitus: XENDOS(Orlistat),
DREAM(Rosiglitazone), DREAM(Ramipril), STOP-NIDDM(Acarbose),
Diabetes Prevention Program(Metformin, Lifestyle Mods), IDPP, FDPS |
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(2008) |
Very brief comparison between the results of ACCORD ( |
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(2008) |
An outline
of the methodology and results of the ACCORD T2DM trial examining the
outcomes (Primary = MI, stroke, CV death) of aggressive lowering of haemoglobin A1C, achieved with various oral hypoglycemics +/- insulin. Trial halted early due to increased mortality in intervention group. |
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(2010) |
This trial summary provides an overview of the blood
pressure-lowering and lipid-lowering sub-trials of the ACCORD T2DM
study. While the main trial examining
intensive glucose-lowering was halted early due to safety concerns, these two
sub-trials were permitted to proceed to their conclusion. The lipid-lowering arm compares open-label Simvastatin 20-40mg/day in
combination with either masked fenofibrate or
placebo at preventing a first
occurrence of major CV events (non-fatal MI or stroke, death from CV causes)
in patients with T2DM and at a high risk of CVD, over a mean period of 4.7
years. The BP-lowering arm compared
the effects of intensive
therapy targeting (SBP≤120mmHg) vs. standard therapy targeting (SBP≤140mmHg) at preventing these same primary endpoints
for the same duration. Results of
these two sub-studies again seem to emphasize that an aggressive approach to
managing chronic diseases does not always translate into improved patient
outcomes – another reminder that the
target should suit the patient, not vice versa. |
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(2008) |
Summary of
the findings of the ADVANCE T2DM trial that aimed to determine whether there are
any outcome benefits (Primary = nephropathy, retinopathy, CV death, nonfatal
MI/stroke) to intensive glucose control achieved by a gliclazide
regimen as compared to a non-gliclazide regimen. |
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(2007) |
A “pros
vs. cons” approach to the growing body of evidence, including the Nissen, Wolski Meta-analysis
(NEJM MAY 2007), linking rosiglitazone to an increased risk of MI and CV
death. Yet another illustration of the
possible harm associated with intensive blood glucose-lowering therapy. |
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(2007) |
An analysis
of the international DREAM trials, which focused on people with impaired
fasting glucose or impaired glucose tolerance and are at low risk of CV
events. The study aimed to determine
whether the use of rosiglitazone 8mg/day or ramipril
15mg/day showed any benefit in slowing the development
and progression of diabetes in this demographic,
when compared to a placebo. |
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GLARGINE & CANCER (2009) |
This
document offers an explanation of the concerns surrounding insulin glargine (Lantus),
a long-acting synthetic insulin analogue.
It also presents the strengths and weaknesses of the studies linking
this drug to cancer, and whether or not these new findings have relevance to
the diabetic population as a whole. (Excerpted with permission from Rapid Rx
July 10, 2009) |
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(2009) |
A non-inferiority
trial whose purpose was to determine whether the addition of
rosiglitazone(4-8mg/day) to a regimen already consisting of either metformin(≤2550mg/day)
or a sulfonylurea(glyburide≤15mg/day; gliclazide≤240mg/day;
glimepiride≤4mg/day) would show a benefit (Primary = CV death or CV
hosp) over a regimen of metformin + a sulfonylurea. |
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(2013) |
Saxagliptin
was non-inferior to placebo in patients at high risk for experiencing
cardiovascular events when considering the primary composite endpoints of
cardiovascular death, non-fatal MI, and non-fatal ischemic stroke. Secondary
and safety endpoints were not positive and some, such as admissions for heart
failure, raised concern of increased harm. Additional trial data is required
before the long term balance of benefit and harm with the incretin agents is
known. |
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(2016) |
Lixisenatide
vs. placebo: not too bad but nothing really good either (not currently available in · Neutral CV effects · SAE no worse than placebo but
discontinuation rates are higher in treatment group · GI adverse events leading to
discontinuation: NNH=28 |
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(2016) |
Empaglifozin
compared to placebo in T2DM population at high risk of CV events resulted in
reduced risk of cardiovascular events (NNT=63/3yrs) and all cause death (NNT=38/3yrs)
despite A1C not reaching target (A1C=7.8%) but caused increased risk of
genitalia infections in males and females (NNH=29 or 14/3yrs) and urosepsis (0.3% ARI) but overall serious AEs were less
with empagliflozin than with placebo (NNT=24). |
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(2016) |
For every
100 patients with recent history of stroke, TIA and insulin resistance
without diabetes, giving pioglitazone 45mg od for ~5 years will result in
approximately 3 less cases of stroke or MI, 4 less cases of diabetes, 2 extra cases of serious bone fracture, 7 extra
cases of weight gain >13.6kg, and 11 extra cases of edema. Given
benefits and harms, secondary prevention with pioglitazone should be
carefully discussed relative to individual values and other alternatives such
as lifestyle intervention. |
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(2016) |
·
Liraglutide
is the first GLP1-A to demonstrate positive CV outcomes in RCT ·
For
every 100 patients on the drug over 4 years will result in 2 less cases of CV events (mostly
death), 2 less cases of nephropathy, 1
extra case of acute gallbladder disease and 2 extra cases of discontinuation
from adverse events ·
Additional
2.3kg weight loss ·
Caution:
previous trials had only neutral results and this drug is rather new to be
certain of long term effects. It is also expensive ($750/ 100 days) |
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(2016) |
·
Sitagliptin
vs. placebo: not too bad but nothing really good either. ·
Neutral
CV effects and no ↑ in HF ·
Caution:
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Some
safety concerns with pancreatitis ·
Cost
is $300/ 100 days for a reduction of 0.3% A1C. |
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Trial |
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(2003) |
An outline of
the purposes and findings of the following trials: AASK, ALLHAT, ALLHAT LLT,
CALM, CAPPP, ELITE II, FACET, HOPE, HOT, IDNT, INSIGHT, IRMA II, LIFE,
NORDIL, OPTIMAAL, PROGRESS, QUIET, RENAAL, SHEP, STOP-Hypertension 2,
SYST-EUR, UKPDS, Val-HeFT |
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(2008) |
To judge
efficacy of ACE Inhibitor (Benazepril 20-40mg/day) + Amlodipine 5-10mg/day
vs. Benazepril 20-40mg/day + Hydrochlorothiazide 12.5-25mg/day in preventing
CV death, non-fatal MI, and stroke in high-risk hypertensive patients. |
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(2010) |
This trial summary
provides an overview of the blood pressure-lowering and lipid-lowering
sub-trials of the ACCORD T2DM study.
While the main trial examining intensive glucose-lowering was halted
early due to safety concerns, these two sub-trials were permitted to proceed
to their conclusion. The
lipid-lowering arm compares open-label Simvastatin 20-40mg/day in combination
with either masked fenofibrate or placebo at
preventing a first occurrence of major CV events (non-fatal MI or stroke,
death from CV causes) in patients with T2DM and at a high risk of CVD, over a
mean period of 4.7 years. The
BP-lowering arm compared the effects of intensive therapy targeting (SBP≤120mmHg)
vs. standard therapy targeting (SBP≤140mmHg) at preventing these same
primary endpoints for the same duration.
Results of these two sub-studies again seem to emphasize that an
aggressive approach to managing chronic diseases does not always translate
into improved patient outcomes – another reminder that the target should suit
the patient, not vice versa. |
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(2003) |
Designed
to determine if there were any clinical outcome differences (Primary =
non-fatal MI and fatal CHD) in high-risk hypertensive patients treated with
relatively newer antihypertensive agents (amlodipine, lisinopril,
doxazosin) versus a low-dose diuretic (chlorthalidone). |
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(2003) |
Compares
the findings of the ANBP2 trial ( |
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(2005) |
Blood
Pressure-Lowering Arm of ASCOT, to determine effect of amlodipine +/-
perindopril vs. atenolol +/-
bendroflumethiazide on ‘non-fatal MI and fatal CHD’
in moderate risk (eg. diabetes 27%) hypertensive
patients without previous heart disease. |
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(2010 Members Only) |
Updated and
condensed summary of the following trials, including the “current knowledge”
obtained from each: AASK, ALLHAT, ASCOT-BPLA, CALM, CAPPP, ELITE II, FACET,
HOPE, HOT, IDNT, INSIGHT, IRMA II, LIFE, NORDIL, OPTIMAAL, PROGRESS, QUIET,
RENAAL, SHEP, STOP-hypertension, SYST-EUR, UKPDS, Val-HeFT |
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(2015) |
A lower BP
target of <120mmHg vs. a standard target of <140mmHg in those at high CV
risk, but without diabetes or stroke, resulted in a trade-off between benefit
& harm. The intensive group experienced lower rates of fatal and
non-fatal CV events but were at higher risk of adverse events. Intensive
targets are sometimes an option with careful patient selection and shared
decision making regarding potential benefits and harms. |
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For patients
with recent symptomatic, MRI-Identified lacunar stroke: ·
Lowering
systolic BP to <130mmHg compared to 130-149mmHg, over 3.7 years, did NOT reduce recurrent stroke ·
SBP
<130mmHg may decrease
intracerebral hemorrhage in a small number of patients without
significantly increased SAE related to hypotension or blood pressure
management ·
At
this time, the Canadian Stroke Best Practices Recommendations 2014 do not
recommend BP <130 mmHg. They recommend a target of <140/90mmHg for
patients who have had a stroke or TIA. |
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Trial |
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(2014) |
To add, or not to add ezetimibe (Ezetrol) to moderate dose statin. Proposed that ezetimibe
may modestly lower CV event risk when added to a moderate dose statin
(simvastatin 40mg). Preliminary data has shown that its addition to moderate
dose statin therapy lowers CV event risk in very high risk patients. However,
higher dose statins have been proven to lower risk in very high risk patients
in a shorter time frame. In those prone to statin intolerance, avoiding high
dose statins may provide a tolerability advantage. The value of adding
ezetimibe is questionable from a cost-benefit perspective. |
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(2011) |
Pattern of CVD changes as CKD progresses: early CKD
cholesterol dependent atheromatous coronary disease; late CKD vascular
calcification, LVH. Lipid lowering therapy (statin) is indicated to prevent
atherosclerotic CVD in patients with CKD including those progressing to ESRD;
findings emphasize need to treat early in disease process, however, point at
which patients may no longer benefit remains unclear, and there is no
evidence to support initiation of statin therapy in dialysis patients.
Studies confirm that statin therapy is safe in late stage CKD. Role of
ezetimibe is not clear, but unlikely to have contributed to clinical
outcomes. |
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(2011) |
AIM-HIGH does
NOT provide support for the use of ER niacin (NIASPAN) as an add on to statin
therapy in a stable 2° prevention population already treated with ASA,
beta-blockers, ACEi or ARB’s & statins. However
likely was not designed appropriately to answer this question since ambitious
estimated risk reduction, and early stop/short duration of the trial. Results
for AIM-HIGH raise questions regarding modifiable nature of residual risk in
patients reaching LDL targets on a statin. |
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(2004) |
Provides a summary chart and general
interpretation of the following lipid trials: 4S, PROVE-IT, HPS, WOSCOPS, |
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(2010) |
This trial summary provides an overview of the
blood pressure-lowering and lipid-lowering sub-trials of the ACCORD T2DM study. While the main trial examining intensive
glucose-lowering was halted early due to safety concerns, these two
sub-trials were permitted to proceed to their conclusion. The lipid-lowering arm compares open-label
Simvastatin 20-40mg/day in combination with either masked fenofibrate
or placebo at preventing a first occurrence of major CV events (non-fatal MI
or stroke, death from CV causes) in patients with T2DM and at a high risk of
CVD, over a mean period of 4.7 years.
The BP-lowering arm compared the effects of intensive therapy
targeting (SBP≤120mmHg) vs. standard therapy targeting (SBP≤140mmHg)
at preventing these same primary endpoints for the same duration. Results of these two sub-studies again seem
to emphasize that an aggressive approach to managing chronic diseases does
not always translate into improved patient outcomes – another reminder that
the target should suit the patient, not vice versa. |
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(2003) |
An overview of the ASCOT-LLA trial, which aimed
to determine if there is any benefit to using
atorvastatin(10mg/day)+antihypertensive meds vs. a placebo +antihypertensive
meds in preventing clinical outcomes (Primary = fatal CHD, non-fatal MI) for
high-risk hypertensive patients. |
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(2004) |
The CARDS trial was designed to judge the efficacy
of atorvastatin(10mg/day) vs. a placebo in preventing CV disease outcomes
(Primary = time to 1st occurrence of: CHD death, non-fatal MI (including
silent), hospitalized for unstable angina, resuscitated cardiac arrest,
coronary revascularization or stroke) for patients with T2DM and at least one
other CVD risk factor. |
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(2008) |
This is a short(24 month) study comparing the effects
of simvastatin(80mg/day) + ezetimibe(10mg/day) vs. simvastatin(80mg/day) + a
placebo by using a surrogate marker (Primary = mean change in carotid artery intima-media thickness)
in patients with elevated LDL levels and heterozygous familial hypercholesteremia. |
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(2015) |
If one wants to lower CV risk in a female with diabetes,
a statin would still have evidence supporting a first line role. Fenofibrate would be reasonable in a female with T2DM who
was unable to take a statin, or in whom achieving specific TC and HDL targets
was specifically desired. |
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(2006) |
The IDEAL trial focuses on a comparison of
high-dose atorvastatin(40-80mg/day) vs. low- to moderate-dose
simvastatin(20-40mg/day). It’s aim is
to determine whether one regimen is superior to the other in preventing
clinical outcomes (Primary = coronary death, non-fatal acute MI, or cardiac
arrest with resuscitation) for patients with history of MI. |
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(2008) |
An international trial that aimed to show the
benefit of using rosuvastatin(20mg/day) vs. a
placebo in preventing
both clinical and surrogate outcomes (Primary = MI, stroke, arterial revascularization, hospitalization for unstable
angina or death from CV causes) in low- to moderate-risk older adults with
normal LDL and elevated C-reactive protein levels. |
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(2004) |
PROVE-IT sought to examine the difference of
efficacy in preventing hard clinical outcomes (Primary = all cause mortality, MI, unstable angina,
revascularization, or stroke) between high-dose atorvastatin(80mg/day) vs.
moderate-dose pravastatin(40mg/day) when either is added to the standard
therapy for patients hospitalized with acute coronary syndrome. |
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(2006) |
This study examines the benefit of using
high-dose atorvastatin(80mg/day) vs. a placebo in preventing clinical
outcomes (Primary = non-fatal or fatal stroke) for patients who have recently
suffered a stroke or
transient ischemic attack and have normal LDL and no known history
of coronary heart disease. |
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(2010 Members Only) |
A concise summary - including comparative graphs,
primary/secondary endpoints, results, and brief analysis – of the following
trials: 4S, LIPID, CARE, HPS, BIP, VA-HIT, CARDS, ASCOT, WOSCOPS, AFCAPS,
HHS, WHO-CLOF. |
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Trials |
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RACE-II |
In a
relatively low risk population, lenient rate control was as effective as
strict rate control for preventing cardiovascular events in patients with
permanent atrial fibrillation (AF). The targeted resting heart rate (HR) for
the lenient control group was set for <110 beats per minute (bpm) and
<80bpm for the strict control group, and the mean resting HR by the end of
the study was 85±14bpm and 76±14bpm, respectively. Less stringent rate
control was not more harmful, and may be beneficial. The lenient rate control
strategy group target was easier to achieve, with fewer medications, lower doses
and less physician visits. The Canadian Cardiovascular Society Atrial
Fibrillation Guidelines recommend a target resting HR of <100bpm for
patients with persistent or permanent AF and atrial flutter. |
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PALLAS |
In a high
risk population with permanent atrial fibrillation (AF), dronedarone
should NOT be added on to standard therapy due to ↑ risk of several
adverse outcomes such as cardiovascular death, stroke and heart failure (HF).
Study was terminated early due to safety concerns. |
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PIONEER AF-PCI |
Patients with
AF and PCI who received rivaroxaban 15mg daily + P2Y12 inhibitor, or
rivaroxaban 2.5mg BID + DAPT had a lower risk of clinically significant
bleeding, experienced no difference in major cardiovascular events (composite
of death from CV causes, MI, or stroke) or stent thrombosis compared to
warfarin+ DAPT (though not powered for this outcome- clinical efficacy
remains uncertain). |
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Trial |
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(2009) |
The purpose of the ACTIVE-A trial was to
determine whether Aspirin(75-100mg/day) + clopidogrel(75mg/day) is superior
to Aspirin(75-100mg/day) + a placebo in preventing a composite of major
vascular outcomes (Primary = stroke, non-CNS systemic embolism, MI, death
from any cause) in patients with atrial fibrillation and at least one other
risk factor for stroke (most pts had CHADS 1-2). Of Note: Over the median 3.6 year follow-up, NNT=42 to
prevent 1 stroke, NNH=42 to cause major bleeding. The ACTIVE-W trial focuses on a similar
patient demographic (most CHADS 2), but was designed to determine whether the
combination of Aspirin(75-100mg/day) + clopidogrel(75mg/day) is superior to a
Vit K antagonist (warfarin, titrate to INR 2-3) in
preventing similar clinical outcomes. ACTIVE-W trial halted early due to
warfarin showing less harm and more benefit than the combo of Aspirin + clopidogrel. Together, the ACTIVE trials make a strong
case for the use of ASA
only for low-risk patients and warfarin only for high-risk patients. |
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ASPIRE |
In patients
with history of an unprovoked venous thromboembolism and low to moderate
bleed risk, the addition of aspirin 100mg daily is reasonable for the
prevention of future venous thromboembolisms and major vascular events if the
decision is made to stop oral anticoagulation. |
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ARISTOTLE |
Apixiban vs
warfarin in patients with Atrial Fibrillation. In 18,201 patients over 1.8yrs with a CHADS2
score of ~2.1, apixapan was superior to warfarin,
without the need for INR monitoring. Apixiban is
not approved for use in |
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(2006) |
The CHARISMA trial was also concerned with the
comparative efficacy of ASA(75-162mg/day) + clopidogrel(75mg/day) vs.
ASA(75-162mg/day) + a placebo in preventing clinical outcomes (Primary =
death from any cause, stroke) in patients at high-risk of atherosclerotic events
and who have CVD or multiple CVD risk factors. Of note: Over the 28 month follow-up, NNT=250 to prevent
1 stroke, while NNH=125 to cause moderate bleeding (safety endpoint). |
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(2009) |
This document is a Q&A reflection on some of
the recent evidence that shows a drug-interaction between clopidogrel
(Plavix) and proton pump inhibitors, especially omeprazole and
esomeprazole. Included are sections offering
the proposed mechanism(s) of this interaction, a discussion of the supporting
evidence, and some tips on managing patients who may be at risk of this
interaction. |
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(2016) |
A group of highly selected patients (56% excluded
at randomization) received a DES (27% paclitaxel) and DAPT beyond 1 year (30
months in total) had less
stent thrombosis (NNT=100) and major adverse CV and cerebrovascular events
(NNT=63) but increased
risk of moderate-severe bleeding (NNH=112) and all cause morality (NNH=200 at
33 months from noncardiovascular causes).
The ideal duration of DAPT therapy is still unknown but extended DAPT therapy
maybe be more beneficial in those who are at very high risk of ischemic
events and low risk of bleeding (were not studied in this trial). |
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(2016) |
STEMI patients treated with fibrinolytics
and DAPT (ASA+ clopidogrel) vs. ASA alone. After PCI, patients had decreased risk of CV death, recurrent
MI or stroke for 30 days (NNT=39). Individual components did not reach
significance. No difference
in major or minor bleeding risk. |
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(2016) |
NSTEACS patients treated with DAPT (clopidogrel +
ASA) vs. ASA alone. They had decreased risk of CV death, MI and urgent revasculization within 30 days of PCI (NNT=53) which was
driven by a decreased risk of MI (NNT=59). Also, these patients had decreased
risk of CV death, MI and revascularization after PCI to end of follow-up
(mean 8 months with NNT=30) which was also driven by a decreased risk of MI
(NNT=53). These benefits were only associated with an increase in minor
bleeds (NNH=72). |
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(2016) |
· Patients are treated with dual antiplatelet therapy
(DAPT, e.g. ASA + clopidogrel, ticagrelor or prasugrel) for 1 year after ACS. Stable patients (i.e.
>1 year after ACS) may benefit from continued DAPT with a low dose of ticagrelor (60 mg BID) + ASA beyond 12 months. Caution in
patients with an ↑risk of bleeding, or a
history of COPD, asthma, or HF due to ↑risk of dyspnea. · In PEGASUS-TIMI 54, patients with history of MI (1-3
years prior) treated with ticagrelor 60 mg BID +
ASA versus ASA alone for a median of 33 months had: 94% were on clopidogrel x
1 year after their index MI · In the fall
of 2015, the U.S. FDA approved ticagrelor 60mg BID
for ↓ the risk of CV death, MI or stroke in
patients with a history of MI. As of April |
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(2016) |
Patients with a high risk of
thrombosis and low risk of bleeding may benefit from Ticagrelor.
Caution in those with a history of COPD, asthma, HF, gout & severe renal
impairment due to increased risk of dyspnea & elevated serum uric acid
& creatinine. In PLATO, ACS
patients (~60% NSTEACS) who received ticagrelor +
ASA, versus clopidogrel + ASA, for a median of 9 months had: ·
↓ risk composite of death from vascular
causes, MI, stroke (NNT=53) ·
Individual components of the composite:
vascular death (NNT=91), MI (NNT=91), stroke (NS) ·
↑ risk of non-CABG related major
bleeding (NNH=167) & fatal bleeding (non-intracranial NNH=500,
intracranial NNH=1112) · ↑
risk of dyspnea (NNH=17), & premature discontinuation of therapy (NNH=53) |
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MATCH |
For high risk patients with
recent stroke or TIA, DAPT with clopidogrel + ASA, compared to clopidogrel alone, initiated
within 3 months of index event, for 18 months, ·
Did NOT reduce ischemic stroke, MI, vascular death or rehospitalization for acute ischemic event. ·
Clopidogrel
+ ASA increased life threatening, major and minor bleeds. ·
Clopidogrel + ASA should not be
combined long-term for secondary prevention of high risk ischemic stroke,
which is consistent with the Canadian Stroke Best Practices Recommendations
2014, and American 2014 Guidelines, which recommend monotherapy (ASA or clopidogrel) or dipyridamole + ASA. |
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SPS3
Antiplatelet Trial (2017) |
For patients with recent,
symptomatic, MRI-identified lacunar stroke, ·
DAPT with clopidogrel + ASA, compared to ASA alone, over 3.4
years, did not reduce
recurrent stoke but
increased all-cause mortality and major extracranial hemorrhage ·
Clopidogrel + ASA should not be
combined long-term for secondary prevention of lacunar strokes, which is
consistent with the Canadian Stroke Best Practices Recommendations 2014, and
American 2014 Guidelines, which recommend monotherapy (ASA or clopidogrel) or dipyridamole + ASA. |
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(2017) |
In Chinese patients with minor
ischemic strokes or high-risk TIA, seen within 24hr of symptom onset who received
clopidogrel + ASA for 21 days then clopidogrel alone for a total of 90 days,
compared to ASA alone for 90 days, had decreased risk of recurrent stroke. ·
Canadian Stroke Best Practice
Recommendations 2014 are cautious
on recommending this routinely for the general Canadian population,
and they await the results of the POINT trial (clopidogrel + ASA vs ASA alone
x 90 days in North America, Australia, and Europe). The use of ASA alone, clopidogrel alone or dioyridamole
+ ASA are preferred for secondary stroke prevention. ·
If choosing to use results from
CHANCE, only a small number (12%) of Chinese patients may benefit. Therapy
must be given within 24 hours of symptom onset, and the dosing regimen
followed, for patients at low risk for bleeds with minor ischemic stroke or
high risk TIA who did not receive thrombolysis. |
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(2010) |
The RE-LY trial compares the benefits and risks
over two years of
Dabigatran 110mg BID or 150mg BID vs. dose-adjusted warfarin (INR 2-3)
as long-term anticoagulant agents in patients with atrial fibrillation, who
are also at increased risk of stroke.
Results of this trial show Dabigatran 110mg BID to be non-inferior vs. warfarin
at preventing the primary endpoints (stroke or systemic embolism), while Dabigatran 150mg BID was shown to
be both non-inferior and superior to warfarin at preventing these
endpoints. These benefits are
accompanied by an increased frequency of dyspepsia in patients receiving
either dose of Dabigatran, and the 150mg BID dose also showed a significantly
higher frequency of GI bleeding.
However, patients receiving warfarin showed higher rates of life threatening,
intracranial (the primary safety endpoint), and minor bleeding than patients
receiving either dose of Dabigatran.
This summary aims to help the reader use the data provided by RE-LY to
make practical choices that lead to the optimal drug therapy for each
individual patient. |
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(2011) |
The ROCKET-AF trial sought to compare the novel
anticoagulant Rivaroxaban
20mg OD (15mg in pts with CrCl=30-49µmol/L) vs.
dose-adjusted warfarin (INR2-3) to reduce stroke or systemic embolism in
high-risk patients (avg CHADS2=3.5) with
persistent/paroxysmal atrial fibrillation. Over the 1.9 year mean follow-up time, rivaroxaban was found to
significantly reduce hemorrhagic stroke and systemic embolism, with lower
rates of intracranial/critical/fatal bleeding compared with warfarin. However, rivaroxaban showed increased rates of GI bleed, Hgb decline (≥20g/L), hematuria, and nosebleeds. The trial was designed to assess outcomes using
both intention-to-treat as well as per protocol analysis, allowing
rivaroxaban to be compared with warfarin for both non-inferiority as well as
superiority. While rivaroxaban was shown to be
non-inferior compared to warfarin for the primary endpoint, the data did not
reach significance for superiority.
While the results of the trial are promising, the high cost
(~$560/month) and lack of both an antidote as well as long-term safety data
for this new agent seem to indicate that warfarin will still have a place in
therapy for the foreseeable future. |
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(2010 Members Only) |
A link to our latest “Oral Antiplatelet &
Antithrombotic Agents” chart from the newly released 8th
Edition Drug Comparison Chart Book (May 2010). Includes most common therapeutic options
and their indications, as well as detailed info on dosing, side effects,
contraindications, and so much more! |
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WARFASA |
In patients with hisotry
of an unprovoked venous thromboembolism with low to moderate bleed risk, the
addition os aspirin 100mg daily is reasonable to
prevent future deep vein thrombosis if the decision is made to stop a vitamin
K+ antagonist. However, in patients at high risk for recurrence, extended
anticoagulation should be considered first line. |
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(2016) |
· In
patients without a history of stroke/TIA, prasugrel
may benefit those with a high risk of thrombosis and a low risk of bleeding. ·
In TRITON-TIMI 38, patients with moderate
to high-risk ACS (74% NSTEACS) undergoing PCI treated with a P2Y12
inhibitor x 14.5 months: -Prasugrel
decreased risk of CV death,
nonfatal MI, & nonfatal stroke (NNT=46), which was primarily which was primarily driven by nonfatal MI
(NNT=44) -No
difference in mortality (CV or all-cause) or stroke · Prasugrel also had decreased risk of urgent target-vessel
revascularization (NNT=84) & stent-thrombosis (NNT=77) significant for
DES & BMS subgroups -
But prasugrel ↑ risk of bleeding:
major non-CABG TIMI (NNH = 167), life-threatening (NNH = 200) and fatal bleeding (NNH= 334) ·
Post hoc analysis of subgroups with net
clinical harm or no net benefit: -History of
stroke/TIA resulted in net harm: CV death, MI, stroke & major bleeding
(non-CABG relate and increased
risk of intracranial bleeding) NNH=15 -Age ≥75, weight < 60kg and
history of stroke/TIA= no net benefit |
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PEGASUS-TIMI 54 |
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Trial |
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(2017) |
In SHIFT, patients with stable moderate to severe
HF-rEF (NYHA Class II 49%, Class III 50%,; mean
LVEF 29%) in sinus rhythm & a resting HR ≥70bpm treated with
ivabradine, compared to placebo, had ↓ risk of CV death or hospital
admission for worsening of HF (ARR 5%, NNT=20/1.9years), driven by
hospitalization, as CV & all-cause mortality alone were non-statistically
significant. This benefit was most prominent in those with a baseline HR of ≥77bpm,
& primary endpoint was NS for those on ≥50% of target β-blocker.
Adverse events included ↑risk of symptomatic bradycardia (NNH=25),
asymptomatic bradycardia (NNH=20), phosphenes
(NNH=50), & AF (NNH=100). Either ivabradine or digoxin may be considered as
an add-on to HF triple therapy to further ↓ HR. The β-blocker should
be titrated to the target or maximally tolerated dose prior to adding either
of these agents. |
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(2015) |
Summary of the PARADIGM-HF Trial which evaluated
to use of an ARNI with an ACEI to determine impact on global mortality and
morbidity in heart failure. Sacubritil or LCZ696’s
efficacy looks promising, but post-marketing data will help determine its
exact role in Heart Failure treatment. New agent may be an option for those
who can’t tolerate ACEI/ARBs + B-Blocker and who aren’t experiencing
symptomatic hypotension.
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(1998) |
A brief summary of the results from the
international ATLAS trial, which sought to distinguish whether an
ACE-inhibitor (lisinopril) was more effective at low
doses (2.5-5mg/day) or high doses (32.5-35mg/day) in preventing clinical
outcomes (Primary = death from any cause) for patients with NYHA Class II-IV
congestive heart failure. |
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(2003) |
The CHARM set of trials are designed to determine
whether the use of an Angiotensin Receptor Blocker (candesartan ~24mg/day)
along with standard therapy could prevent clinical outcomes (Primary = death from
all causes) in patients with heart failure.
CHARM-Alternative focuses on the use of ARB’s in patients that are
intolerant of ACE-inhibitors. The
CHARM Added wing of the study attempts to show a benefit to using ARB’s in
addition to ACE-inhibitors in patients with heart failure. Lastly, the CHARM Preserved arm examines
whether there is any benefit to using ARB’s in patients with preserved
left-ventricular function |
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Trial |
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(2002) |
A findings summary for the WHI (Women’s Health
Initiative) trials, which aims to determine the long-term effects of
conjugated equine estrogen (Premarin, 0.625mg/day)
+ medroxyprogesterone (Provera, 2.5mg/day) in otherwise older, healthy
postmenopausal women. WHI focuses on
clinical outcomes (Primary = CHD, invasive breast cancer) to weigh the
benefits and drawbacks of combination HRT.
The summary also references several findings of the similar HERS/HERS
II study, which focused on patients who already had CHD. All three studies trend toward the same
conclusion – the risks
of long-term HRT may in fact outweigh the benefits in many postmenopausal
women. Finally, a chart is
included that describes various approaches to HRT and the evidence (or lack
thereof) supporting each, followed by a sampling of alternative therapeutic
options to alleviate symptoms and risk factors common to postmenopausal
women. WHI trial halted early due to risk-benefit
imbalance. |
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(2002) |
A further breakdown of the WHI trial findings,
paying particular attention to how the age of trial participants may
influence an interpretation of the results.
Also included is a discussion as to why an apparently small increase
in breast cancer incidence from HRT must be weighed against other factors to
gain a full appreciation of risk vs. benefit. |
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(2002) |
Yet another analysis of the data provided by the
WHI trials, focusing on the primary study outcomes (CHD, invasive breast
cancer) that eventually led to the early termination of the experiment. Also includes a useful “Tips in
Interpreting Data” section that can (and should!) be applied to any study. |
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Trials |
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(2010) |
Provides a brief outline of the
various etiologies resulting in anemia, followed by a summary of the
intervention, population, and results of the following studies: ∙ Iron Trials – Charytan et al, Van Wyck et al, DeVita et
al, Besarab et al, Macdougall et al, Fishbane et al, DRIVE-I, DRIVE-II ∙
ESA Trials –
Revicki et al, Levin et al, CREATE, CHOIR, Canadian EPO Study Group, Parfrey
et al, Foley et al, Besarab, Tonelli et al, TREAT Also offers points to consider for both Iron and
ESA therapy of chronic kidney disease, either with or without dialysis |
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Trials |
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(2006) |
Offers an overview, with interpretive comments,
of the population, intervention, and results for the following trials: SMART,
Wolfe, Rabe, STAY, GOAL, Concept, Overbeek, START, Ram, Gibson, Ni, Adams(Cochrane), Lasserson(Cochrane), Masoli(Fluticasone),
Masoli(Budesonide), IMPACT |
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FLAME |
This trial compares the effectiveness of indacaterol + glycopyrronium (ULTIBRO
BREEZHALER) and salmeterol + fluticasone (ADVAIR) in patients with
moderate-to-severe COPD and >1 COPD exacerbations in the past year.
Indacaterol + glycopyrronium
did significantly decrease mild-moderate exacerbations, improved quality of
life and had less adverse events compared to salmeterol + fluticasone. |
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Trial |
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(2018) |
· Patients with chronic non-cancer pain (CNCP) – (back
pain or osteoarthritis of the hip or knee) did as well or better on a
strategy that favored a non-opioid stepped approach to therapy compared to an
opioid stepped approach (relatively low-dose). - No difference in functional outcomes - Pain intensity was worse in the opioid strategy
arm than the non-opioid arm (NNH = 8) - Adverse events were more common in the opioid
strategy arm · Significant
improvements in both pain and function was seen in both groups, possibly
related to both being allowed the same access to non-pharmacologic
interventions, and both had frequent follow-up visits and/or phone calls. · Patients in the opioid group saw a greater reduction
in anxiety score |
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(2018) |
This trial compares Opioid vs Nonopioid
Single Dose Medications for Acute Extremity Pain in the Emergency Department
(ED) -administration of a single dose nonopioid combination (ibuprofen + acetaminophen) vs.
oral opioid combinations [(oxycodone + acetaminophen), (hydrocodone +
acetaminophen), (codeine + acetaminophen)] -Adverse event information was not collected and
contextualization of results requires consideration of those who may not be
suitable candidates (e.g. see exclusions) for an NSAID + acetaminophen based
regimen -For moderate-severe acute pain, opioid analgesic
combinations do not outperform nonopioid
combinations. Unless NSAID + acetaminophen combination is contraindicated, it
is an excellent pharmacological choice for acute extremity pain in the ED. |
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CATIE-AD |
This trial compares the effectiveness of atypical
antipsychotics drugs ( risperidone, quetiapine & olanzapine to placebo)
in 421 patients for up to 36 weeks. There was no significant differences between
any atypical agents & placebo for overall rate of discontinuation. These agents offer limited efficacy, but
differ in their side effect profile. |
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(2001) |
Summary of several studies that looked at the
efficacy of various COX-2 inhibitors, including: ∙
MELISSA –
Meloxicam(7.5mg/day) vs. Diclofenac(100mg SR/day) ∙ SELECT – Meloxicam(7.5mg/day) vs. Piroxicam(20mg/day) ∙ CLASS – Celecoxib(800mg/day) vs.
Ibuprofen(2400mg/day) vs. Diclofenac(150mg/day) → Each class treatment arm was separated
into two subgroups, one receiving ASA(≤325mg/day) and one receiving no ASA ∙ VIGOR – Rofecoxib*(50mg/day)
vs. Naproxen(1000mg/day) |
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(2008) |
This trial summary looks at a study (Kay et al.)
comparing Darifenacin(7.5-15mg/day) vs.
Oxybutynin(10-20mg/day) vs. a placebo in improving memory recall outcomes
(Primary = Name-Face Association Test score) for otherwise healthy older
patients. The main purpose of the
study was to justify the use of Darifenacin over
oxybutynin to treat urinary incontinence based on the newer drug’s improved
side-effect profile (lower cognitive impairment). This document also offers some insight into
why the limitations of this study design prevent such a definitive
justification. |
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As a supplement to our newsletter, Q&A summary, and CFP article on opioid use for chronic non-cancer pain,
this trial summary provides an overview of a recent observational cohort
study examining the relative efficacy and safety of NSAID’s, Coxib’s, and opioids in elderly patients (84% women) with
arthritis and <2 comorbidities. The
article offers some advice toward individualizing therapy for this difficult
condition, and gives some interpretation of some of the more ambiguous data
presented in the article. Notably, a
comment on the clinical significance of increased rates for CV events, mortality,
fracture, and GI obstruction within the opioid cohort, and which of
these adverse events should be of primary concern to caregivers. |
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(2013) |
The primary conclusion that can be drawn from
this study is that neither solifenacin nor
oxybutynin was associated with significant changes from baseline in any of
the five standard, composite outcomes of cognitive function. Given the
limited potential for any differences between the agents, and the substantially higher
cost, an initial trial of oxybutynin is preferred. |
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Varenicline & Increased CV Risk (2011) |
In July 2011 there was a meta-analysis published
in the CMAJ attributing an increased risk of serious cardiovascular events to
varenicline (CHAMPIX in |
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Varenicline
for Smoking Cessation in Schizophrenia or Bipolar: 52 vs 12 weeks (2014) |
Smokers with mental illness tend to have higher
rates of regular tobacco use, nicotine dependence and quit attempts than
smokers without mental illness. This trial summary evaluates the length of
tobacco abstinence with maintenance pharmacotherapy of 52 weeks vs the
standard treatment of 12 weeks in people with schizophrenia and bipolar
disorder. Results show that the use of varenicline for 1 year may decrease
tobacco dependence and smoking related morbidity/mortality in those with
serious mental illness. Although initial response to varenicline was good,
abstinence decreased over time. Due to the small sample size, it is difficult
to accurately assess the risk of serious AE or make safety claims about neuropsychiatric
symptoms/events or CV risk. |
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With Health |
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In adult primary care patients with
lower-respiratory tract infections (LRTI) where pneumonia is not suspected,
amoxicillin 1g po TID x 7 days, versus placebo, did
not decrease the duration of symptoms or decrease symptom severity within the
first 2-4 days. However, amoxicillin did decrease new or worsening symptoms (NNT=30) but did increase
the risk of adverse events (NNH=22).
This study does not change how acute LRTIs are managed in adults when pneumonia
is not suspected. Antibiotics are not recommended because of limited to no
benefit & increased risk of harm. |
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CAP-START (2017) |
In patients from the |
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Nitrofurantoin vs
Trimethoprim-Sulfamethoxazole in Women with Acute Uncomplicated Cystitis
(2017) |
Women with acute uncomplicated cystitis were
randomized to open-label treatment with either trimethoprim-sulfamethoxazole
(TMP-SMX) for 3 days or nitrofurantoin for 5 days. Nitrofurantoin was equally
efficacious to TMP-SMX and had a similar rate of adverse effects. Five days
of nitrofurantoin is a very effective and safe first-line option in this
patient population. Also of note, three days of TMP-SMX has a similar
clinical cure rate even though pathogens were less susceptible. In fact,
TMP-SMX worked 2/3rds of the time even in those where culture results
suggested non-susceptible. |
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Clindamycin versus
Trimethoprim-Sulfamethoxazole for Uncomplicated Skin Infections
(2017) |
In this trial of healthy patients with
uncomplicated skin and soft tissue infections (SSTIs), there were no
significant differences in efficacy or adverse events between clindamycin and
trimethoprim-sulfamethoxazole. In patients with skin infections and MRSA risk
factors, either TMP-SMX or clindamycin may be efficacious depending on
resistance rates. However, MRSA resistance to clindamycin is often higher in
the real world than in this study. In |
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* Note: Rofecoxib withdrawn from market in
2004 due to increased CV risk |
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