creation date: 2025-10-16 12:05
tags:
High Impact Studies in Medicine
CONSENSUS 1987
Findings
Use of enalapril (ACEi) reduced mortality and improved symptoms in patients with severe congestive heart failure.
4 “S” Study 1994
Scandinavian Simvastatin Survival Study
Findings
Use of simvastatin reduced death compared to placebo in patients with CHD:
- All-cause: RR 0.7
- Coronary deaths: RR 0.58
37% reduction of risk of myocardial revascularization need.
NINDS Trial 1995
Findings
Use of IV t-PA within 3 hours of onset of ischemic stroke improved clinical outcome at three months.
This is despite findings of increased incidence of symptomatic intracerebral hemorrhage.
No benefit (complete resolution of neurologic deficit or improvement from baseline by NIHSS score of ≥4) was observed at 24 hours compared to placebo.
Background
Prior to study, tPA used with significant caution due to IC hemorrhage. Prior studies using lower doses in very early treatment showed neurologic improvement prompting further investigation.
Study Appraisal
Internal validity
| Criteria | Acceptable? | Comments |
|---|---|---|
| Focused | Y | |
| Randomized | Y | Stratified by time from onset of stroke |
| Blinded | Y | Outcomes determined by examiners not present at treatment, CT reviewed by radiologist without clinical information for compliance. |
| Similar baseline | Y | Except for weight (in 24h post-tx) and age & aspirin use for 3 month analysis. |
| Equal treatment | Y | Placebo protocol explicitly stated but implied to follow same bolus and infusion procedure. |
| Loss to follow-up | Y | 90%+ compliance to protocol. Deceased participants were given worst possible scores in data analysis. |
| ITT analysis | Y | All analysis based on ITT |
| External validity |
| Criteria | Notes |
|---|---|
| Conflict of interests | |
| Applicable population | Inclusion: -Ischemic stroke with measurable NIHSS scale deficit -No evidence of IC hemorrhage on CT Exclusion: -PMHx stroke/serious head trauma in past 3 months -PMHx IC hemorrhage -PMHx GI hemorrhage, urinary tract hemorrhage in past 21 days -PMHx of arterial puncture at noncompressible site in past 7 days -Major surgery past 14 days -SBP >185 or DBP >110 -Suspicion of SAH -Seizure at onset of stroke -Taking anticoagulants or had heparin within 48h preceding stroke and had elevated PTT -PTT >15s, platelets <100,000, or glucose <2.7 or >22.2 -If aggressive antihypertensive therapy needed |
| Benefit vs. costs | Favourable outcomes across NIHSS, modified Rankin, and Glasgow outcome scale indicating minimal or no disability. Risk of symptomatic intracranial bleed which resulted in deaths. Occurred more in t-Pa treated patients with more severe deficits at baseline. |
| Clinically important outcomes | t-Pa treatment used within 3 hours of ischemic stroke onset improved clinical outcomes at 3 months. |
RALES 1999
Findings
Use of spironolactone (aldosterone-receptor antagonist) in conjunction with ACEi in CHF patients compared to placebo had:
- Cardiac cause death RR 0.69
- All cause death RR 0.70
The reduction is risk of death consistent across analyses based on serum K, NYHA class, use of K supplements, use of beta-blockers, and geographic regions.
More patients saw reduction in NYHA class and fewer patients saw worsening in the spironolactone group compared to placebo
The trial was ended early as the benefits of spironolactone exceeded prespecified values.
Background
Aldosterone is important in the pathophysiology of heart failure. Prior to this study, treatment of CHF with LVEF consisted of ACEi, loop diuretic, and digoxin.
tor blocker is also relatively contraindicated due to risk of hyperkalemia.
Study Appraisal
Internal validity
| Criteria | Acceptable? | Comments |
|---|---|---|
| Focused | Y | |
| Randomized | Y | |
| Blinded | Y | Double blinded to matched placebo |
| Similar baseline | Y | |
| Equal treatment | Y? | Protocol in place for side effects of tx arm but appears to have been applied to control too |
| Loss to follow-up | Y | Pts who stopped treatment were still included in analysis |
| ITT analysis | Y | |
| External validity |
| Criteria | Notes |
|---|---|
| Conflict of interests | |
| Applicable population | Inclusion: -NYHA class IV within 6 months prior to enrolment and class III or IV at environment -Diagnosed at least 6 weeks prior -Treated with ACEi (if tolerated) and loop diuretic (digitalis and vasodilator also ok, potassium-sparing diuretics not ok) -LVEF ≤35% Exclusion: -PMHx of Primary operable valvular heart disease, congenital HD, unstable angina, primary hepatic failure, active cancer, any life-threatening disease -Hx heart transplant or waiting procedure -Serum creatinine >221 mcmol/L -Serum K >5 mmol/L |
| Benefit vs. costs | Slight risk of hyperkalemia but very insignificant relative to benefit |
| Clinically important outcomes | Reduction in death, reduced cardiac remodelling when used with ACEi |
HOPE 2000
Heart Outcome Prevention Evaluation
Findings
In patients with vascular disease or diabetes and with cardiovascular risk factor(s), ramipril reduced:
- Death from cardiovascular causes (RR 0.74)
- MI (RR 0.80)
- Stroke (RR 0.68)
- All cause death (RR 0.84)
- Revascularization procedures (RR 0.85)
- Cardiac arrest (RR 0.63)
- Heart failure (RR 0.77)
- Diabetic complications (RR 0.84)
NNT = ~15
Background
RAAS is implicated in risk of cardiovascular events. Prior research had shown ACEi is beneficial in patients with low ejection fraction. This study addresses use of ACEi in patients beyond those with low ejection fraction.
Study Appraisal
Internal validity
| Criteria | Acceptable? | Comments |
|---|---|---|
| Focused | Y | |
| Randomized | Y | |
| Blinded | Y | Double-blinded (10mg v. 2.5mg v. placebo) |
| Similar baseline | Y | |
| Equal treatment | Y | |
| Loss to follow-up | Y | |
| ITT analysis | Y | ~30% discontinued in both arms but included in analysis |
| External validity |
| Criteria | Notes |
|---|---|
| Conflict of interests | |
| Applicable population | Inclusion: -≥55 years old -Hx of CAD, stroke, peripheral vascular disease, or diabetes + one other cardiovascular RF Exclusion: -Hx of HF, or low ejection fraction (<40%) -Taking ACEi or vitamin E -Uncontrolled hypertension or overt nephropathy -PMHx MI or stroke within 4 weeks prior to study |
| Benefit vs. costs | |
| Clinically important outcomes | Use of ACEi reduced CV events. |
MERIT – HF 2000
Metoprolol controlled/Extended-release Randomized Intervention Trial in congestive Heart Failure
Findings
In patients with chronic HF with NYHA class II-IV and ejection fraction ≤40% incidence of the following were lower in the metoprolol CR/XL group than placebo:
- All-cause mortality/hospitalization (RR 0.81)
- All-cause mortality/hospitalization due to worsening heart failure (RR 0.69)
- Death or heart transplantation (RR 0.68)
- Cardiac death or nonfatal acute MI (RR 0.61)
The study was terminated at halfway point as predefined criterion was met and exceeded.
Background
Study Appraisal
Internal validity
| Criteria | Acceptable? | Comments |
|---|---|---|
| Focused | Y | |
| Randomized | Y | |
| Blinded | Y | Single-blinded placebo run in period, double-blind placebo controlled trial |
| Similar baseline | Y | |
| Equal treatment | Y | |
| Loss to follow-up | Y | |
| ITT analysis | Y | |
| External validity |
| Criteria | Notes |
|---|---|
| Conflict of interests | |
| Applicable population | Inclusion: -Symptomatic HF for ≥3 months -NYHA class II-IV and LVEF ≤40% -LVEF 36-40%: symptomatic minimum cutoff -Age 40-80 Exclusion: -Acute MI or unstable angina within 28 days before randomization -Indication or contraindication for treatment with beta-1 blockade -Severe decompensated HF (eg. pulmonary edema) -Supine SBP <100 mmHg |
| Benefit vs. costs | |
| Clinically important outcomes | Use of metoprolol CR/XL once daily in addition to conventional HF treatment reduced worsening HF and need for hospitalization. |
Heart Protection Trial 2002
Findings
In patients with coronary disease, other occlusive arterial disease, or diabetes, use of simvastatin compared to placebo reduced:
- All-cause mortality (RR 0.877)
- Death from vascular causes (RR 0.835)
- Death from coronary causes (RR 0.82)
Background
Prior trials (incl. the 1994 4S Study) showed use of statins reduced coronary mortality and morbidity in certain high-risk patients. Little evidence was available for patients on other high-risk groups such as patients with diabetes but without diagnosed coronary disease, females, elderly, and those with lower LDL-C concentrations.
Study Appraisal
Internal validity
| Criteria | Acceptable? | Comments |
|---|---|---|
| Focused | Y | |
| Randomized | Y | |
| Blinded | Y | |
| Similar baseline | Y | |
| Equal treatment | Y | |
| Loss to follow-up | Y | |
| ITT analysis | Y | Accounts for non-study statins prescribed due to increased LDL which were either addition to study dose or placebo |
| External validity |
| Criteria | Notes |
|---|---|
| Conflict of interests | |
| Applicable population | Men and women aged 40-80 years old with non-fasting total cholesterol of ≥3.5 mmol/L and at substantial 5-year risk of death from CAD due to PMHx. |
| Benefit vs. costs | |
| Clinically important outcomes | Statins reduced all-cause mortality for secondary prevention following cardiovascular event |
AFFIRM 2002
Atrial Fibrillation Follow-up Investigation of Rhythm Management
Findings
In patients with atrial fibrillation, rhythm control offered no survival advantage compared to rate control (HR 1.15 (CI: 0.99-1.34, P=0.08)).
The rhythm group had more hospitalization and more adverse drug effects.
Background
Current treatment paradigms allows for two approaches to treatment of atrial fibrillation:
- Cardioversion followed by antiarrhythmics to maintain sinus rhythm
- Use of rate-controlling medications and allowing afib to persist
In both case, anticoagulants are indicated.
Study Appraisal
Internal validity
| Criteria | Acceptable? | Comments |
|---|---|---|
| Focused | Y | |
| Randomized | Y | |
| Blinded | N | Treatment option choices was decided by treating physician, thus clinicians aware of which arm. Additionally, rhythm and rate control are symptomatically different. |
| Similar baseline | Y | |
| Equal treatment | N? | Rhythm control arm required cardioversion |
| Loss to follow-up | Y | |
| ITT analysis | Y | Cross-over rate from each arm analyzed and deemed acceptable |
| External validity |
| Criteria | Notes |
|---|---|
| Conflict of interests | |
| Applicable population | Patients ≥65 years old or had other risk for stroke or death. Atrial fibrillation must have been assessed to likely be recurrent, likely to cause illness or death, and long term treatment was warranted. |
| Benefit vs. costs | |
| Clinically important outcomes | Use of rate-control was not inferior to rhythm control. When accounting for adverse effects, may be superior. |
ACTIVE W 2006
Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events
- ACTIVE A = Clopidogrel + aspirin vs. placebo + aspirin
- ACTIVE W = Clopidogrel + aspirin vs. oral anticoagulation
- ACTIVE I = Irebesartan with ACTIVE A or W participants
Findings
In patients with atrial fibrillation, clopidogrel and aspirin compared to oral anticoagulation therapy saw higher risk of:
- Stroke (RR 1.72)
- Non-CNS systemic embolism (RR 4.66)
- Minor bleeds
Comparison saw similar rates of:
- Total mortality (RR 1.01, CI 0.81-1.26; p=0.91)
- Major hemorrhage
Background
Atrial fibrillation increases the risk of stroke and other vascular events. Oral anticoagulation typically consisted of warfarin which was shown to reduce risk of stroke and CV events significantly. However, risk of major bleeding increased by 70% compared to just aspirin.
Additionally, warfarin required regular INR monitoring.
Study Appraisal
Internal validity
| Criteria | Acceptable? | Comments |
|---|---|---|
| Focused | Y | |
| Randomized | Y | |
| Blinded | N | Open treatment but blinded adjudication of outcomes |
| Similar baseline | Y | |
| Equal treatment | N | Open treatment + INR measurement |
| Loss to follow-up | Y | |
| ITT analysis | Y | |
| External validity |
| Criteria | Notes |
|---|---|
| Conflict of interests | |
| Applicable population | Inclusion -ECG evidence of afib -At least one of the following: → Age 75 or older → On treatment for htn → Previous stroke, TIA, or non-CNS systemic embolus → LVEF <45% → PAD → Age 55-74 if diabetes or CAD Exclusion -CI for medications -Peptic ulcer disease in previous 6 months -PMHx IC hemorrhage -Significant thrombocytopenia -Mitro stenosis |
| Benefit vs. costs | |
| Clinically important outcomes | Oral anticoagulation therapy is superior to clopidogrel + aspirin for afib pervention of stroke |
Rosiglitazone and Risk of MI/Death
Effect of Rosiglitazone on Risk of Myocardial Infarction and Death from Cardiovascular Causes
Findings
In a meta-analysis of clinical trials relating to rosiglitzone with outcome data (MI and death from cardiovascular causes):
Patients who received rosiglitazone, compared to those with a non-rosiglitazone comparator, had:
- Increased risk of myocardial infarction (OR 1.43, 95CI 1.03-1.98)
- Increased risk of death (OR 1.64, 95CI 0.98-2.74)
Effect: rosiglitazone is no longer used.
Limitations
Limited access to original source data - no time-to-event analysis.
Background
Thiazolidinedione drugs were widely used as antihyperglycemic agents in treatment of type 2 diabetes.
At the time of study, troglitazone was already removed from use prior to this study due to hepatotoxicity, with rosiglitazone and pioglitazone remaining on the market.
Study Appraisal
| Criteria | Acceptable? | Additional Comments |
|---|---|---|
| Internal validity | Y No funnel plot, Jadad scores , | |
| External validity | Y |
HYVET 2008
Findings
In patients who are 80 years of age or older (mean BP 173/91), treatment with antihypertensive therapy (mean BP 15/6 lower than placebo) compared to placebo reduced:
- Rate of fatal or nonfatal stroke (RR 0.70)
- Rate of death from stroke (RR 0.61)
- Rate of all-cause death (RR 0.79)
- Rate of death from cardiovascular causes (RR 0.77)
- Rate of heart failure (RR 0.36)
Background
It is well-established that antihypertensive therapy is beneficial in many subpopulations. However, the benefits of treating older patients is inconclusive.
Prior studies have shown elevated BP is associated with:
- Risk of stroke
- Risk of death
However, epidemiologic studies have shown BP and risk of death are inversely related among people aged 80 or older, possibly suggesting risk of antihypertensive therapy or conditions associated with BP reduction (cancer, dementia, MI, HF).
Study Appraisal
Internal validity
| Criteria | Acceptable? | Comments |
|---|---|---|
| Focused | Y | End points: stroke (not incl. TIA), death from various causes/all causes |
| Randomized | Y | |
| Blinded | Y | Double |
| Similar baseline | Y | |
| Equal treatment | Y | Including “adjustment” dose placebo |
| Loss to follow-up | Y | |
| ITT analysis | Y | |
| External validity |
| Criteria | Notes |
|---|---|
| Conflict of interests | |
| Applicable population | Inclusion -Aged ≥80 -Persistent htn (SBP>160) Exclusion -CI to meds -Accelerated or secondary htn -Hemorrhagic stroke in previous 6 months -HF requiring antihypertensive treatment -Serum creatinine >160 mcmol/L -Serum K <3.5 or >5.5 mmol/L -Gout -Diagnosis of clinical dementia -Required nursing care |
| Benefit vs. costs | |
| Clinically important outcomes | Treatment with sustained release indapamide ± perindopril beneficial in terms of adverse outcomes |
PLATO 2009
PLATelet inhibition and patient Outcomes
Findings
In patients with ACS, use of ticagrelor with aspirin compared to clopidogrel with aspirin reduced the occurrence of:
- Death from vascular causes, MI, or stroke (HR 0.84)
- Death from composite of cardiac/vascular causes (HR 0.88)
The groups did not differ significantly in terms of rates of major bleeding.
Background
Prior clinical practical guidelines recommend dual antiplatelet treatment for patients with ACS. This consist of aspirin and clopidogrel.
Clopidogrel requires a slow and variable prodrug to active metabolite mechanism which results in nonideal platelet inhibition.
Tricagrelor is an reversible and direct-acting antagonist of P2Y12 which provides better inhibition than clopidogrel.
Study Appraisal
Internal validity
| Criteria | Acceptable? | Comments |
|---|---|---|
| Focused | Y | |
| Randomized | Y | |
| Blinded | Y | |
| Similar baseline | Y | |
| Equal treatment | Y | |
| Loss to follow-up | Y | |
| ITT analysis | Y | |
| External validity |
| Criteria | Notes |
|---|---|
| Conflict of interests | |
| Applicable population | -Hospitalized for ACS w/ ST-segment elevation -Hospitalized for ACS w/o ST elevation but with other indicators of acute heart disease (eg. troponin, ST changes, PMHx) -Onset of symptom within 24 hrs |
| Benefit vs. costs | |
| Clinically important outcomes | Superior performance of primary end points of ticagrelor vs clopidogrel with similar rates of major bleed. |
ACTIVE A 2009
Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events
- ACTIVE A = Clopidogrel + aspirin vs. placebo + aspirin
- ACTIVE W = Clopidogrel + aspirin vs. oral anticoagulation
- ACTIVE I = Irebesartan with ACTIVE A or W participants
Findings
In patients with atrial fibrillation unsuitable for vitamin K-antagonist therapy, use of clopidogrel + aspirin compared to just aspirin reduced:
- Risk of stroke (RR 0.72)
- Risk of vascular events (0.89)
Use of clopidogrel increased risk of major bleed (RR 1.57).
Background
Atrial fibrillation increases the risk of stroke and other vascular events. Oral anticoagulation typically consisted of warfarin which was shown to reduce risk of stroke and CV events significantly.
Study Appraisal
Internal validity
| Criteria | Acceptable? | Comments |
|---|---|---|
| Focused | Y | |
| Randomized | Y | |
| Blinded | Y | |
| Similar baseline | Y | |
| Equal treatment | Y | |
| Loss to follow-up | Y | |
| ITT analysis | Y | |
| External validity |
| Criteria | Notes |
|---|---|
| Conflict of interests | |
| Applicable population | -Diagnosed afib -Risk factor(s) for stroke -Unable to use vitamin K antagonist |
| Benefit vs. costs | |
| Clinically important outcomes |
ROCKET AF 2011
Rivaroxaban Once-daily oral direct factor xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation
(Rivaroxaban Once-daily Compared with vitamin K antagonism for prevention of stroke and Embolism Trial)
Findings
In patients with nonvalvular atrial fibrillation and increased risk of stroke, use of rivaroxaban compared to dose-adjusted warfarin reduced:
- Occurrence of stroke or systemic embolism (HR 0.79, ITT HR 0.88)
Similar rates of major and nonmajor clinically relevant bleeding (HR 1.03, CI 0.96-1.11).
Background
Atrial fibrillation associated with risk of stroke. Vitamin K antagonists (warfarin) are effective at stroke prevention but require frequent INR monitoring and dose adjustments.
Rivaroxaban is a direct factor Xa inhibitor that is more consistent at anticoagulation than warfarin.
Study Appraisal
Internal validity
| Criteria | Acceptable? | Comments |
|---|---|---|
| Focused | Y | |
| Randomized | Y | |
| Blinded | Y | |
| Similar baseline | Y | |
| Equal treatment | Y | Yes including fake INR values for rivaroxaban arm |
| Loss to follow-up | Y | |
| ITT analysis | Y | |
| External validity |
| Criteria | Notes |
|---|---|
| Conflict of interests | |
| Applicable population | Inclusion: -Non-valvular atrial fibrillation -Moderate to high risk for stroke |
| Benefit vs. costs | |
| Clinically important outcomes |
ARISTOTLE 2011
Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation.
Findings
In patients with nonvalvular atrial fibrillation and increased risk of stroke, use of rivaroxaban compared to dose-adjusted warfarin reduced:
- Occurrence of stroke or systemic embolism (HR 0.79, p<0.001 for noninferiority, p=0.01 for superiority)
- Rate of major bleed (HR 0.66)
- Rate of death (HR 0.89)
Background
Atrial fibrillation associated with risk of stroke. Vitamin K antagonists (warfarin) are effective at stroke prevention but require frequent INR monitoring and dose adjustments.
Apixaban is a direct factor Xa inhibitor that is more consistent at anticoagulation than warfarin.
Study Appraisal
Internal validity
| Criteria | Acceptable? | Comments |
|---|---|---|
| Focused | Y | |
| Randomized | Y | |
| Blinded | Y | |
| Similar baseline | Y | |
| Equal treatment | Y? | Unclear if INR for apixaban group was checked |
| Loss to follow-up | Y | |
| ITT analysis | Y | |
| External validity |
| Criteria | Notes |
|---|---|
| Conflict of interests | |
| Applicable population | Inclusion: -Afib or aflutter with 2 episodes prior -Risk factor for stroke Exclusion: -Afib was due to reversible cause -Mod/severe mitral stenosis -Other conditions requiring anticoag -Need for antiplatelet or severe renal impairment |
| Benefit vs. costs | |
| Clinically important outcomes | Apixaban is superior to warfarin for prevention of stroke or systemic embolism, caused less bleeding, and resulted in lower mortality |
CRASH 2013
Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage-2
Findings
In adult patients with either
- significant hemorrhage (SBP <90, HR >110, or both)
- at risk of significant hemorrhage and within 8 hours of injury
without clear indication for or against use of TXA, use of TXA (1g over 10 min then 1g over 8 hours) compared to placebo, resulted in:
- Reduced all cause mortality (RR 0.91)
- Reduced death due to bleeding if administered within 3 hours (RR 0.85)
- Early treatment, ≤1 hour from injury: RR 0.68
- Treatment between 1-3 hours: RR 0.79
- Late treatment after 3 hours: RR 1.44
- No difference in blood product transfusion requirements
Limitations
Background
Exsanguination is common cause of death in trauma patients. In major surgery (which trigger similar hemostatic response to trauma), a fibrinolytic response occurs which can become pathological (hyper-fibrinolysis).
Antifibrinolytic agents have been shown to reduce blood loss in patients with fibrinolytic responses to surgery without increasing risk of complications (eg. VTE).
A number of antifibrinolytics exist, but TXA has been used previously for bleeding trauma and thus selected for the trial.
Associated studies are:
- CRASH-1: Corticosteroid use after significant head injury
- CRASH-3: Antifibrinolytic in significant head injury
Study Appraisal
| Criteria | Acceptable? | Additional Comments |
|---|---|---|
| Internal validity | Y | Telephone randomization wasn’t used in some low-resource settings |
| External validity | Y |
PARADIGM 2014
Prospective comparison of ARni with Acei to Determine Impact on Global Mortality and morbidity in heart failure trial
Findings
In adult patients with reduced ejection fraction heart failure, use of sacubitril/valsartan (Entresto), an angiotensin receptor-neprilysin inhibitor, compared to an ACEi reduced:
- All cause mortality (HR 0.84)
- Cardiovascular causes mortality (HR 0.80)
- Risk of hospitalization for HF by 21%
Study ended prematurely due to overwhelming benefit.
Background
Established treatment for CHF have included ACE inhibitors for decades (see CONSENSUS 1987). Angiotensin-receptor blockers have been thought to be equivalent, although the evidence is less consistent, and has thus been used in patients who have ACEi-associated side effects.
Neprilysin degrades endogenous vasoactive peptides (natriuretic peptides, bradykinin, adrenomedullin) which causes vasoconstriction, sodium retention, and maladaptive remodelling. Inhibition of neprilysin would counter this.
Entresto is a combination of an ARB and neprilysin inhibitor.
Study Appraisal
| Criteria | Acceptable? | Additional Comments |
|---|---|---|
| Internal validity | Yes | |
| External validity | Yes |
SPRINT 2015
Systolic blood PRessure INtervention Trial
Findings
Along patients with high risk of cardiovascular events (but without diabetes/prior stroke), a systolic blood pressure target of <120 mmHg compared to a target of <140 mmHg reduced:
- Cardiovascular events (ACS, stroke, HF, death from CVD) (HR 0.75)
- All-case mortality (HR 0.73)
Risk of adverse events were higher in the lower target group:
- Hypotension (HR 1.67)
- Syncope (HR 1.33)
- Electrolyte abnormalities (HR 1.35)
- Acute kidney injury (HR 1.66)
Limitations
Study population limited to those with:
- Age ≥50
- Increased risk of cardiovascular events (CKD, >15% on Framingham score, age ≥75)
The study also excluded patients with either:
- Diabetes
- Prior stroke
Background
Treatment of hypertension reduces risk of cardiovascular outcomes. However, the target SBP was uncertain with studies suggesting risk begins with SBP above 115 to 150 mmHg.
Study Appraisal
| Criteria | Acceptable? | Additional Comments |
|---|---|---|
| Internal validity | Y | |
| External validity | Y |
EMPA-REG-OUTCOME 2015
EMPAgliflozin Removal of Excess Glucose: cardiovascular OUTCOME event trial in type 2 diabetes mellitus patients
Findings
In adult patients with type 2 diabetes at high risk of cardiovascular events, use of empagliflozin, an SGLT2 inhibitor, compared to placebo, saw reduced:
- Death from cardiovascular causes, nonfatal MI, or nonfatal stroke (composite; HR 0.86)
- Death from cardiovascular causes (RR 0.62)
- Hospitalization from heart failure (RR 0.65)
- All cause mortality (RR 0.68)
The intervention group saw higher rates of genital infection but no imbalance for uncomplicated or complicated UTI.
Background
While type 2 diabetes and cardiovascular disease both increase the risk of death, evidence for the benefit of glucose lowering therapy on reducing cardiovascular events and death has been unclear.
In particular, prior antihyperglycemics have caused adverse cardiovascular events (rosiglitazone) and thus addition vigilance was required.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce blood glucose levels by increasing urinary glucose excretion. Other effects included:
- Weight loss
- Reduction in blood pressure without increases in heart rate
- Favourable effect on markers of arterial stiffness and vascular resistance
Study Appraisal
| Criteria | Acceptable? | Additional Comments |
|---|---|---|
| Internal validity | Y | |
| External validity | Y |
PECARN DKA FLUID 2018
Clinical Trial of Fluid Infusion Rates for Pediatric Diabetic Ketoacidosis (Kuppermann et al.)
Findings
In patients aged <18 years old with a diagnosis of DKA, the rate of infusion (rapid vs. slow) and sodium content (0.45% vs. 0.9%) did not differ significantly for:
- Magnitude of GCS score decrease
- Incidence of clinically apparently brain injury
- Memory and IQ scores obtained after recovery
- Occurrence of serious adverse events
Limitations
Exclusion criteria:
- Underlying disorders affecting mental status testing
- Concurrent alcohol/narcotics use, head trauma, or other neurologic conditions
- Known pregnancy
- GCS ≤11
Background
Prior to study, fluid administration has undergone several evolutions, such as the introduction of slow rehydration with isotonic fluids to prevent cerebral edema.
Infusion rates varied based on centres, with numerous infusion protocols requiring calculations for rate of administration and sodium chloride content.
Study Appraisal
| Criteria | Acceptable? | Additional Comments |
|---|---|---|
| Internal validity | Y | |
| External validity | Y |
TAVR Low-Risk Trials 2019
Transcatheter Aortic-Valve Replacement with a self-expanding valve in Low-Risk patients
Findings
In patients with severe aortic-valve stenosis with a low risk of death (≤3% predicted), use of a transcatheter aortic valve replacement (TAVR) instead of surgery saw:
- Reduced risk of death or disabling stroke at 24 months (RR 0.79)
- Lower incidence of:
- Disabling stroke
- Bleeding complications
- Acute kidney injury
- Atrial fibrillation
TAVR had:
- Lower aortic-valve gradients
- Larger effective orifice area
TAVR increased the risk of:
- Moderate or severe regurgitation
- Pacemaker implantation
Limitations
- Study only did 12 month follow up
- Bicuspid valves or those candidates for mechanical valves were excluded
Background
TAVR was shown to be effective and noninferior for patients at intermediate surgical risk. However, patients with low surgical risk were not included for TAVR as surgical risk was low enough compelling evidence was required before TAVR was attempted for this population.
Study Appraisal
| Criteria | Acceptable? | Additional Comments |
|---|---|---|
| Internal validity | Y | End-point data collection was not fully blinded for all end points |
| External validity | Y |
RECOVERY 2020
Randomized Evaluation of COVid-19 thERapY trial
Findings
In patients hospitalized for SARS-CoV-2 infection, addition of oral or intravenous dexmethasone to usual treatment resulted in:
- Reduced death among those receiving mechanical ventilation (RR 0.64)
- Reduced death among those receiving supplemental oxygen without invasive mechanical ventilation (RR 0.82)
- No effect on those not receiving respiratory support (RR 1.19 (CI 0.92-1.55))
Note that the categorization by use of ventilation and oxygen are that at randomization.
Limitations
Unknown true effect of use in patients not receiving respiratory support (suggests possible harm or no effect).
Background
Severe Covid-19 infection in early 2020 resulted in high mortality and increased risk of needing invasive mechanical ventilation. At the time of the study, no therapeutic agents have been shown to reduce mortality.
Study Appraisal
| Criteria | Acceptable? | Additional Comments |
|---|---|---|
| Internal validity | Y | Randomization was completed without age stratification but analysis was made with stratification for prognostication |
| External validity | Y | |
| Findings in this trial has been further confirmed by meta-analysis. |
EMPEROR PRESERVED 2021
EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure with PRESERVED ejection fraction
Findings
In adults with HFpEF (EF>40%, HYHA II-IV; NT-proBNP >300 or >900 if concurrent afib), use of empagliflozin compared to placebo, saw:
- Reduced composite death from cardiovascular causes or hospitalization of HF (HR 0.79)
- Reduced hospitalization for HF (HR 0.71)
- Reduced death from cardiovascular causes (HR 0.91)
- Reduced rate of decline of GFR (-1.25 vs. -2.62 mL/min/1.73m2/year)
- No difference in all cause mortality (HR 1.00)
Benefit is consistent across subgroups, with or without diabetes. It is also consistent with findings of EMPEROR-Reduced, suggesting SGLT2i benefits do not depend on heart failure phenotype.
Limitations
High rate of discontinuation (23% in both groups) due to reasons other than death may have skewed effect to the null hypothesis resulting in the lack of effect on all-cause mortality.
Background
SGLT2 inhibitors have been show to reduce development and progression of HF in patients with type 2 diabetes and progression in patients with HFrEF. Findings have been inconclusive for those with HFpEF.
Study Appraisal
| Criteria | Acceptable? | Additional Comments |
|---|---|---|
| Internal validity | Y | |
| External validity | Y |
STEP1 2021
Semaglutide Treatment Effect in People with obesity
Findings
In adult patients
- unsuccessful in dietary efforts to lose weight
- without diabetes or pancreatitis
- BMI of ≥30 or ≥27 with a weight-related comorbid condition
use of once weekly 2.4 mg subcutaneous semaglutide (0.25 mg initially x4wk increased every 4 weeks until 2.4 mg), compared to placebo saw:
- Greater change in body weight from baseline (-14.9% vs. -2.4%)
- Greater improvement in cardiometabolic risk factors
- Greater increase in participant-reported physical function from baseline
Both groups also received additional lifestyle interventions consisting of reduced-calorie diet and increased physical activity.
Use of semaglutide resulted in increased reported side effects:
- Nausea (44.2% of participants vs. 17.4%)
- Diarrhea (31.5% vs. 15.9%)
- Vomiting (24.8% vs. 6.6%)
- Constipation (23.4% vs. 9.5%)
Limitations
The study had a majority of women (73.1% of treatment arm and 76% of placebo) and White (74.5% of treatment and 76.2% of placebo) patients and excluded patients with type 2 diabetes.
The authors also suggest a potential the participants were a more motivated subgroup than the general population.
Background
Obesity is associated with a number of health concerns. Lifestyle intervention is a cornerstone in management but long-term maintenance of weight loss is challenging and adjunctive pharmacotherapy are limited.
Prior antiobesity drugs are daily, BID, or TID which may affect adherence.
Semaglutide is a GLP-1 agonist used for type 2 diabetes. It was found to induce weight loss in adults with obesity and type 2 diabetes (phase 2 STEP). It is available once weekly and has shown to be beneficial for weight loss (SCALE study).
Study Appraisal
| Criteria | Acceptable? | Additional Comments |
|---|---|---|
| Internal validity | Y | |
| External validity | Y |
SELECT 2023
SEmagLutide Effects on Cardiovascular ouTcomes in people with overweight or obesity
Findings
In adults ≥45 years of age with a BMI ≥27 and established cardiovascular disease and without diabetes, use of a once-weekly subcutaneous semaglutide at 2.4 mg (initial 0.24 mg increased q4wk to 0.5, 1.0, 1.7, then 2.4) compared to placebo, resulted in:
- Reduced composite death (cardiovascular causes, nonfatal MI, nonfatal stroke) (HR 0.80)
- Decreases in body weight and waist circumference
- Increased incidence of serious adverse events leading to discontinuation (eg. GI disorders)
Limitations
Study only included patients with preexisting cardiovascular disease. Population of study also skewed away from women (27.7%) and Black (3.8%) patients, which is lower than general population.
Background
Overweight and obesity are independently associated with an increased risk of cardiovascular events, even after accounting for metabolic cardiovascular RFs linked to excess weight.
Previous methods for reducing cardiovascular risk include treating dyslipidemia, hypertension, and diabetes. However, treatment of obesity to reduce cardiovascular complications is limited.
GLP-1 agonists are used in the management of type 2 diabetes and obesity. However, whether there is a dirrect effect on reduction of cardiovascular risk is unknown. Studies in animals have shown:
- Reduced inflammation
- Improved endothelial and LV function
- Improved plaque stability
- Decreased platelet aggregation
Study Appraisal
| Criteria | Acceptable? | Additional Comments |
|---|---|---|
| Internal validity | Y | |
| External validity | Y |
BALANCE 2024
Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness
Findings
In admitted patients with a positive blood culture, use of a shorter duration course of antibiotics (7 days) compared to a longer duration (14 days) resulted in:
- Noninferiority relating to 90-day mortality (-1.6%, CI -4.0 to 0.8)
Findings consistent with subsequent smaller trials.
Limitations
Exclusion criteria:
- Severely immunocompromised
- Had prosthetic heart valves or endovascular grafts
- Suspected or documented syndrome requiring prolonged treatment (eg. endocarditis, osteomyelitis, septic arthritis, undrained abscess, or prosthetic-associated infection)
Background
Antibiotic therapy improves survival but duration of treatment is understudied.
Traditionally, short-course antibiotics bring concern for insufficient treatment and thus cause relapsing infection and selection of resistance. However, excessive durations results in avoidable adverse events including C. difficile infection.
Prior studies have found noninferiority of short-course antibiotics (≤7 days) for bacterial infections (HAP and CAP, uncomplicated intraabdominal infection, pyelonephritis, cellulitis) but excluded or did not focus on bacteremia.
Study Appraisal
| Criteria | Acceptable? | Additional Comments |
|---|---|---|
| Internal validity | Y | Consistent results with ITT and PP |
| External validity | Y |
FLUID 2025
A Crossover Trial of Hospital-Wide Lactated Ringer’s Solution versus Normal Saline
Findings
In admitted patients, use of lactated Ringer’s solution compared to normal saline resulted in no significant difference in:
- Composite death or readmission within 90 days (RR 0.97, 95CI 0.90-1.05)
- ED visits within 90 days (RR 1.01, CI 0.88-1.15)
- Hospital length of stay
Limitations
Exclusion criteria:
- Age < 1 month
Only included 7/16 intended hospitals and thus reduced power.
Background
Crystalloid fluids, including normal saline and lactated Ringer’s, are commonly used for treatment.
Lactated Ringer’s is balanced and thus does not contain excess chloride compared to normal saline (aside: NS contains 154:154 mEq/L while plasma contains 140:100). This thus reduce the risk of hyperchloremic acidosis.
Prior studies have found use of balanced crystalloids are associated with lower incidence of adverse kidney events but the evidence has been inconclusive on the effects on mortality.
Study Appraisal
| Criteria | Acceptable? | Additional Comments |
|---|---|---|
| Internal validity | Y | Cluster randomized (hospital-wide intervention selection) and cross-over at wk 15 |
| External validity | Y |
COBRRA 2026
Comparison Of Bleeding Risk between Rivaroxaban and Apixaban for the treatment of acute venous thromboembolism
Bleeding Risk with Apixaban vs. Rivaroxaban in Acute Venous Thromboembolism
Findings
In adult patients with acute VTE, use of apixaban compared to rivaroxaban resulted in:
- Reduced risk of clinically relevant bleeding (RR 0.46)
- Reduced risk of major bleeding (RR 0.16)
- Reduced risk of clinically relevant nonmajor bleeding (RR 0.59)
Note:
- Apixaban had lower adherence (65.7% vs 75.1%)
- 3 month recurrence of VTE was 1% in both group
- Thus, nonadherence does not (necessarily) explain bleeding risk
Limitations
Exclusion criteria:
- GFR <30
- Active bleeding
- Cancer-related (standard of care is LMWH)
- Weight >120 kg
Limitations:
- Findings are from first 3 months, may vary beyond
- Exclusion criteria of obesity
- Not extrapolatable to other indications (VTE secondary prevention, cancer-associated VTE, atrial fibrillation)
Background
DOACs are frequently used for treatment of acute VTE, both acutely and afterwards for prevention of recurrent thrombotic events.
Prior studies have shown DOACs
- Rivaroxaban 15 mg BID x21d followed by 20mg daily
- Apixaban 10mg BID x7d followed by 5mg BID
were noninferior to warfarin but also found differences in bleeding risk (4.3% of apixaban vs. 9.7% of rivaroxaban). These findings were hypothesized to be due to patient populations but definitive comparison was not made.
Study Appraisal
| Criteria | Acceptable? | Additional Comments |
|---|---|---|
| Internal validity | Y | Open-label, but assessment of bleed made by objective criteria |
| External validity | Y |
ARISE FLUIDS 2026
Australasian Resuscitation In Sepsis Evaluation: FLUID or vasopressors in emergency department Sepsis
Findings
In adult patients presenting to the ED with septic shock, use of restricted fluids and early vasopressors, in comparison to liberal fluids and later vasopressors:
- Did not increase days survived out of hospital
- Did not increase mortality at hospital discharge
Limitations
Background
Prior guidelines weakly recommend a dose of IV fluids within 3 hours of recognition of hypotension. However, RCT have been recommended for initial dosing and subsequent fluid strategy. Additionally, no recommendations are made for the timing of vasopressor use.
Study Appraisal
| Criteria | Acceptable? | Additional Comments |
|---|---|---|
| Internal validity | Y | Not blinded (due to nature of intervention) |
| External validity | COI, applicable | |
| Inclusion criteria: |
- SBP <90 or MAP <65 despite 1000 mL fluid from boluses
- Lactate >2.0 mmol/L
- Began treatment with IV abx
- Within 6 hours of presentation to ED and <2000 mL fluid administered