RxFiles:Objective Comparative Drug Information

Trial Summaries









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.




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.




A synopsis of the purposes, parameters, and outcome evidence for the following trials: DCCT, DCCT/EDIC, UKPDS-33, UKPDS-34, Kumamoto, PROACTIVE, ACCORD, ADVANCE, RECORD, STENO, UGDP, VADT, UKPDS-80, FDPS, DPP, IDPP, Stop-NIDDM, XENDOS, DREAM-Rosi, DREAM-Rami, NAVIGATOR


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




Very brief comparison between the results of ACCORD (N. America – glimepiride, metformin, rosiglitazone, insulin) and ADVANCE (Eur/Asia – gliclazide, metformin) trials, which aimed to show the clinical outcomes associated with aggressive lowering of blood glucose in T2DM.  A very good example of why, in terms of drug therapy, more is not always better.




Original Article

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.




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.




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.





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.




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.



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)




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.




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.




Lixisenatide vs. placebo: not too bad but nothing really good either (not currently available in Canada).

·  Neutral CV effects

·  SAE no worse than placebo but discontinuation rates are higher in treatment group

·  GI adverse events leading to discontinuation: NNH=28




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).




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.




·            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)




·            Sitagliptin vs. placebo: not too bad but nothing really good either.

·            Neutral CV effects and no ↑ in HF

·            Caution:

·           Some safety concerns with pancreatitis

·           Cost is $300/ 100 days for a reduction of 0.3% A1C.







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




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.




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.




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).




Compares the findings of the ANBP2 trial (Australia) of ACE Inhibitors (enalapril) vs. diuretic (HCTZ) with those of the ALLHAT trial (N. America) and offers some possible insight as to why they are different.




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.



(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




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.


SPS3 Systolic Blood Pressure Trial (2017)

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.








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.






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.





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.





Provides a summary chart and general interpretation of the following lipid trials: 4S, PROVE-IT, HPS, WOSCOPS, ASCOT





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.





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.





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.





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.



FIELD Substudy


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.





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.





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.





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.





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.




(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.









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.




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.




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).









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.




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.




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 Canada & there is no know antidote for this agent.





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).






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.





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).





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.





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).





· 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 
risk of the composite endpoint (cardiovascular death, MI, stroke) (NNT=79/3 years)
      - individual components of the composite: CV death (NS), MI (NNT=139/3 years), stroke       
        (NNT=213/3 years)
- ↑risk of major bleeding (NNH=81/3 years), & ↑risk of bleeding resulting in discontinuation of  study drug (NNH=22/3 years)
- ↑risk of dyspnea (NNH=11/3 years), & ↑risk of dyspnea resulting in discontinuation of study drug (NNH=27/3 years)
- Benefit was
only seen in patients who had uninterrupted P2Y12 inhibitor therapy or restarted therapy within ≤30 days

·  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 2016, in Canada this is an unapproved indication for ticagrelor & the 60mg strength is currently unavailable.





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)




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.



SPS3 Antiplatelet Trial


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.





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.









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.





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.




(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!




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.



























·  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













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.






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.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             





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.





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









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.



WHI and Age


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.



WHI Extras


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.









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









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




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.









· 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



Chang et al RCT


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.




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.






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

VIGORRofecoxib*(50mg/day) vs. Naproxen(1000mg/day)     





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.



Pain Control in Elderly Arthiritis (2011)

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.





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.



Varenicline & Increased CV Risk


In July 2011 there was a meta-analysis published in the CMAJ attributing an increased risk of serious cardiovascular events to varenicline (CHAMPIX in Canada), which is considered one of the more effective agents available for smoking cessation.  While the study authors rightly assert that their findings indicate a need to reassess the safety profile of varenicline, there has much debate (ex. AAFP, BMJ) as to whether their data is as broadly applicable as they claim.  This article seeks to clarify some of the issues being discussed in regard to varenicline, in order to put forward a slightly more nuanced interpretation of the original data.  Ultimately, it shows that even in the supposed hard science of evidence-based medicine, a NNT can still be a hotly debated subject.



Varenicline for Smoking Cessation in Schizophrenia or Bipolar: 52 vs 12 weeks


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. 



Vick’s Vapor Rub for Cough & Cold (2011)

With Health Canada’s recent recommendation towards more conservative use of OTC cough & cold products in pediatrics, many parents have been left to wonder what they can do to try to relieve these symptoms in their children.  This summary focuses on a trial comparing topical Vapor Rub vs. white petrolatum vs. no treatment for the relief of night-time cough and cold symptoms in kids aged 2-11.  While the study itself is somewhat methodologically limited in the strength of evidence it provides, this article offers some context as to the overall efficacy of treatment with Vapor Rub, and how it fits into cough and cold management.  One interesting stat of note – Vapor Rub was slightly more likely to help the parents of sick children sleep through the night than it was their symptomatic kids – perhaps offering some insight into Health Canada’s more restrictive policies regarding the use of cough and cold products in this age group.



Amoxicillin vs Placebo in patients with acute lower-respiratory tract infection in primary care when pneumonia is not suspected (e.g. bronchitis) (2017)

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.



CAP-START (2017)

In patients from the Netherlands with community acquired pneumonia (CAP) (median CURB-65 Score of 1 [IQR 1-2], mean Pneumonia Severity Index (PSI) ~85 [SD~28]) who were admitted to non-ICU hospital ward, beta-lactam monotherapy was non-inferior to the combination of beta-lactam + macrolide in regards to 90 day mortality. Median length of hospital stay, and major and minor complications were similar between three treatment strategies (beta-lactam, beta-lactam + macrolide, fluoroquinolone).



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.




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 Saskatchewan, MRSA resistance to clindamycin is 30-40%, much higher than the 4% in this study. Thus, TMP-SMX is preferred over clindamycin.



* Note: Rofecoxib withdrawn from market in 2004 due to increased CV risk