Gruppo di Autoformazione Metodologica

Italian guidelines on thrombolysis indications in ischemic stroke have been revised after IST-3 trial and Cochrane revision: cons

One of the milestones of evidence-based medicine is the critical appraisal [1]. Critical appraisal shifts clinical practice from eminence-based medicine (medicine based on authority) to evidence-based medicine (medicine based on the proof and the judgment of the proof). Clinical practice guideline recommendations should be based on the best available evidence. Therapeutic recommendations should be developed upon randomized controlled trials (RCTs) with clinically relevant (defined as ‘‘hard’’) primary end points, low risk of bias, rigorous internal validity and good external validity [2]. The Italian guidelines on thrombolysis indications in ischemic stroke [3] have been revised after the IST-3 trial [4]. Does IST-3 satisfy the above-mentioned RCT characteristics providing the best evidence on which a clinical practice guideline should be modified? When the IST-3 trial was published many considered it the end of the struggle between ‘‘pros’’ and ‘‘cons’’ about thrombolysis [5–7]. Indeed IST-3 is the largest trial on this topic. The Lancet editorial accompanying the IST-3 trial claims ‘‘The role of stroke and emergency physicians is now not to identify patients who will be given rt-PA, but to identify the few who will not’’ [5]. An authoritative IAEM editorial [8] commenting on the IST-3 trial concludes ‘‘We have no longer to ask the age, but just the onset time!’’ However, some weaknesses should be considered [9] and we suggest that there are still some reasons to introduce some notes of caution. If a large trial has some biases, it should not be considered as the ‘‘best’’ evidence and used to change the recommendations of clinical practice guidelines. The aim of this paper is not a comprehensive critical appraisal of the IST-3 trial, already published [10]. We would like just to highlight some major criticisms indicating that maybe the IST-3 trial results are not adequate to change clinical practice.

Colchicine is safe and effective for secondary prevention of recurrent pericarditis.

The CORP (COlchicine for Recurrent Pericarditis) trial [7]is a prospective, randomized, double-blind, placebo controlled, multicenter trial to evaluate the efficacy and safety of colchicine (1.0–2.0 mg on the first day, followed by a maintenance dose of 0.5–1.0 mg/day for 6 months) in association with conventional anti-inflammatory therapy for the secondary prevention of recurrence in patients with a first relapse of pericarditis. Patients were excluded if they were having their first episode of acute pericarditis, or their second or subsequent recurrence, or had pericarditis with tuberculous, purulent, or neoplastic causes. The primary study end point was the recurrence rate at 18 months. Secondary end points were symptom persistence after 72 h, remission rate at 1 week, number of recurrences, time to first recurrence, disease-related hospitalizations,cardiac tamponade, and constrictive pericarditis rates.120 patients (60 in the colchicine and 60 in the placebo group) were included in the analysis. The recurrence rate is 24 % in the colchicine group and 55 % in the placebo group (absolute risk reduction 0.31 [95 % CI 0.13–0.46];relative risk reduction 0.56 [0.27–0.73]; number needed to treat 3 [2–7]). Colchicine improves the persistence of symptoms at 72 h (absolute risk reduction 0.30 [95 % IC,0.13–0.45]; relative risk reduction 0.56 [0.27–0.74]). It also reduces the mean number of recurrences, increases the remission rate at 1 week and prolongs the time to subsequent recurrence. Colchicine and placebo groups have similar rates of side effects (7 %) and drug withdrawal (8 vs. 5 %, P = 0.89);no severe side effects occurred in any of the groups. Gastrointestinal intolerance was the main side effect during the study.

Aspirin in the secondary prevention of unprovoked thromboembolism: the WARFASA and ASPIRE studies

The treatment of unprovoked venous thromboembolism (VTE) is anticoagulant therapy for at least 3 months [1]. As VTE recurs frequently and about 20 % of the patients with an unprovoked VTE develop recurrence within the first 2 years [2], extended vitamin K antagonist (VKA) treatment is often considered. The decision to prolong VKA therapy after the initial treatment period is a dilemma, since longer term therapy reduces the risk of recurrent thromboembolism, but increases the risk of bleeding. The last American College of Chest Physicians (ACCP) EvidenceBased Clinical guidelines suggest a strategy to balance the benefits and risks of different durations of anticoagulant therapy; in unprovoked VTE, ACCP guidelines suggest extended anticoagulant therapy if bleeding risk is low or moderate (Grade 2B) and recommend 3 months of therapy if bleeding risk is high. When extended anticoagulant therapy is contraindicated, aspirin might be appealing. In fact the annual risk of major bleeding is only 0.1 % in patients on long-term low-dose aspirin therapy, thus lower than VKA therapy [3]. A large meta-analysis by the Antiplatelet Trialists’ Collaboration shows that antiplatelet therapy significantly reduces the risk of fatal or non-fatal pulmonary embolism (PE) by 25 % [3]. Moreover, a large trial involving patients undergoing surgery for hip fracture shows a 36 % risk reduction in VTE in the aspirin therapy group, [4] suggesting that antiplatelet therapy may be an alternative to prolonged VKA therapy. Two randomized controlled studies were conducted to evaluate the use of ASA for the prevention of venous thromboembolism recurrence: the Aspirin for the Prevention of Recurrent Venous Thromboembolism (Warfarin and Aspirin [WARFASA]) [5] and the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) study [6].

Can we trust in trials stopped early for benefit

In a multicenter, randomized, placebo-controlled, doubleblind clinical trial, Elmunzer et al. [1] assigned patients at elevated risk for postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis to receive a single dose of rectal indomethacin or a placebo immediately after ERCP. According to the authors’ summary, prophylactic rectal indomethacin significantly reduced the incidence of postERCP pancreatitis (PEP) in patients at elevated risk for this complication. The trial has been stopped early after an interim analysis. Is it reasonable to trust the results of this early stopped trial showing the benefit of indomethacin in preventing PEP? A randomized clinical trial (RCT) is designed and conducted to provide the answer to a relevant clinical question. The protocol of an RCT should report several details on how the researchers are going to conduct the trial. First of all, the aim of the study has to be clear. Secondly, the outcomes (primary and secondary) should be predetermined as the statistical methods used to analyze them. Next, another item to be specified in the protocol is the number of patients to be included in the study. When determining the sample size, investigators should clarify some details about the scientific hypothesis underlying the clinical question they want to answer. Large RCTs are periodically monitored as patients are enrolled, and interim analyses are performed on collected data. Sometimes, the decision of stopping a trial early is adopted as a consequence of the results of an interim analysis. There are several reasons for the early termination of a RCT. First, a trial may be stopped early for harm, if significantly worse outcomes are observed among patients receiving the experimental treatment. Another reason for early termination of a trial may be futility, when it is highly unlikely that the trial will accrue the planned number of patients, or if the interim analysis shows that it is extremely unlikely that any benefit will be seen if the study is continued. Finally, trials may be stopped for a significant benefit in the experimental arm (trial stopped early for benefit). In this case, patients receiving the non-experimental treatment may be allowed to ‘‘crossover’’ and receive the beneficial treatment. In these papers we will only focus on the trials that have been stopped early for benefit. There are several reasons for stopping an RCT for benefit. First of all, the investigators may feel ethically obligated to stop a trial showing an apparent benefit of a study treatment. An individual ethical issue may drive the decision to stop a trial before the end of the randomization of all the planned patients, since it’s considered unethical to deny a study participant an effective treatment. This issue may be compelling for investigators and patients who may be allowed to ‘‘crossover’’, and receive the more beneficial treatment after an interim analysis shows an apparent benefit of the experimental intervention. Beyond the individual ethical issues, there are some collective interests leading to the decision to stop a trial for benefit. If a new treatment is more effective than the older one, it’s a collective interest that study results spread as quickly as possible, making the treatment available for all G. Casazza (&) Dipartimento di Scienze Biomediche e Cliniche ‘‘L. Sacco’’, Universita degli Studi di Milano, Via G.B. Grassi, 74, 20157 Milan, Italy e-mail: giovanni.casazza@unimi.it

Why meta-analyses on the same topic lead to different conclusions?

Berger [1] ‘‘There was no significant reduction for myocardial infarction, stroke, ischemic stroke, or allcause mortality.’’ (all-cause mortality: RR 0.94, 95 % CI 0.89–1.00, p = 0.07). Raju [2] ‘‘Aspirin prevents deaths, myocardial infarction...’’ (deaths: RR 0.94; 95 % CI, 0.88–1.00 p = 0.05). Seshasai [3] ‘‘Modest, but not significant, reductions were observed for total CHD..., total nonvascular mortality..., and all-cause mortality...’’ (all-cause mortality: OR 0.94; 95 % CI, 0.88–1.00).

Can we extend thrombolysis indications for acute ischaemic stroke? The IST-3 study.

BackgroundEach year, about 22 million people have a stroke world-wide, of whom 4 million reside in high-income countries.The burden of ischaemic stroke among the elderly is largeand increasing; it is estimated that annually ischaemicstroke affects about a million people older than 80 years inhigh-income countries and about 3 million in low-incomeand middle-income countries [1].So far intravenous thrombolysis is indicated for patientswith ischaemic stroke, aged less than 80, within 4.5 h fromthe occurence of neurologic signs, without any contrain-dications [2].Since many patients with acute ischaemic stroke,according to current guidelines, cannot be candidatedfor thrombolysis, it would be appealing to extend itsindications.Although thrombolysis has been proved to amelioratemorbidity in acute ischaemic stroke, it increases cerebralhaemorrhage; so, before extending thrombolysis indica-tions, strong evidence of benefits is needed [3].SummaryThe third international stroke trial (IST-3) is a multicentre,pragmatic, open-treatment study which randomised 3,035patients to 0.9 mg/kg intravenous recombinant tissueplasminogen activator (rt-PA) or to control [1].The primary endpoint was the proportion of patientsalive and independent at 6 months, as defined by an OxfordHandicap Score (OHS) of 0–2. The main secondary end-points were mortality and morbidity at 7 days. Initially,there was a pilot phase, double blinded and placebo con-trolled (\10 % pts), and then authors shifted to opentreatment. The eligibility criteria can be summarized interms of the uncertainty principle. Briefly, patients wereeligible according to the following criteria: they hadsymptoms and signs of clinically definite acute stroke; thetime of stroke onset was known; treatment could be startedwithin 6 h of onset; and CT or MRI had reliably excludedboth intracranial haemorrhage and structural brain lesions,which could mimic stroke. In addition, if the patient had aclear indication for intravenous thrombolysis with rt-PA,they were to be treated in accordance with local guidelines.Equally, if the patient had a clear contraindication totreatment, they were not to be entered in the trial. The datawere analysed following the intention-to-treat principles.Of notice that among 3,035 patients enrolled, 95 % didnot meet local European guidelines for thrombolysis, 72 %were treated more than 3 h after stroke onset, 53 % agedmore than 80 and 5 % had a NIHSS greater than 25.At 6 months, 554 (37 %) patients in the rt-PA groupversus 534 (35 %) in the control group were alive andindependent [OHS 0–2; adjusted odds ratio (OR) 1.13,95 % CI 0.95–1.35, p = 0.181). Fatal or non-fatal symp-tomatic intracranial haemorrhage within 7 days occurred in104 (7 %) patients in the rt-PA group versus 16 (1 %) inthe control group (adjusted OR 6.94, 95 % CI 4.07–11.8,p\0.001). More deaths occurred within 7 days in the rt-PA group [163 (11 %)] than in the control group [107(7 %), adjusted OR 1.60, 95 % CI 1.22–2.08, p = 0.001],

Timing of the initiation of parenteral nutrition in critically ill adults

BackgroundCritical illness in hospitalized patients induces anorexia: aninability to eat suitably, predisposing to nutritional deficit,weakness, infections, increased duration of mechanicalventilation, delayed recovery and death [1]. To date,whether artificial nutritional support improves outcomesfor critically ill patients is unclear. Enteral nutrition isassociated with fewer complications than parenteral nutri-tion, and is less expensive [2], but enteral nutrition alonedoes not often achieve caloric targets. Combining paren-teral and enteral nutrition could prevent nutritional deficit.However, this strategy may carry the risk of overfeeding,which has been associated with complications such as liverdysfunction [3]. Current clinical practice guidelines fornutritional support in critically ill patients are largely basedon expert opinion, and differ substantially across conti-nents, in particular about the timing to start parenteralnutrition. The European Society of Parenteral and EnteralNutrition (ESPEN) recommends the commencement ofparenteral nutrition within 2 days after admission to theintensive care unit (ICU) for patients who cannot be ade-quately fed enterally [4], while the American and Canadianguidelines recommend early initiation of enteral nutrition,but suggest starting parenteral nutrition after a week inpatients who are not malnourished at baseline [5].SummaryCasaer and coworkers [6] in a randomized, multicenter trial,comparedanearlytoalateinitiationofparenteralnutritioninadults admitted to the ICU who were not malnourished atbaseline [body-mass index (BMI) of C17] in order to sup-plement insufficient enteral nutrition. The primary endpoints were the number of days spent in ICU (for survivorsand non-survivors), and the time to discharge from the ICU.In 2,312 patients, parenteral nutrition was initiated within48 h after ICU admission, whereas in 2,328 patients, it wasnot initiated before the eighth day from admission. ThemedianstayintheICUwas1 dayshorterinthelate-initiationgroup than in the early-initiation group (3 vs. 4 days,respectively, P = 0.02), which was reflected in a relativeincrease of 6.3% of the likelihood of earlier discharge alivefrom the ICU [hazard ratio 1.06, 95% confidence interval(CI), 1.00–1.13, P = 0.04]. Considering the secondary out-comes, patients in the late-initiation group had fewer healthassistance related infections (22.8 vs. 26.2%, P = 0.008), alowerincidenceofcholestasis(32.6vs.38.4%,P\0.001),areduction in the proportion of patients requiring more than2 days of mechanical ventilation (36.3 vs. 40.2%,P = 0.006), a median reduction of 3 days in the duration ofrenal replacement therapy (7 vs. 10 days, P = 0.008) and areduction in mean health care costs of €1,110 as comparedwith the early-initiation group (€16863 vs. €17973,P = 0.04). The safety outcomes (in-hospital mortality rates,survival at 90 days, rates of nutrition-related complications)weresimilarinthetwogroups,buthypoglycaemiawasmorecommon in the late-initiation group patients (3.5 vs. 1.9%,P = 0.001). Although enteral nutrition was initiated if pos-sible in the majority of patients, the post hoc subgroupanalyses including patients for whom early enteral nutritionwas contraindicated showed the same results.

Eplerenone, an aldosterone antagonist, reduces hospitalization and death in heart failure patients with nyha class II and an ejection fraction of less than 30%

BackgroundThe renin-angiotensin-aldosterone system (RAAS) playsan important role in pathophysiology of heart failure (HF).RAAS blockade with angiotensin converting (ACE)inhibitor slows the progression of HF and improves thesurvival [1]. However, ACE inhibitors do not block themineralocorticoid receptors, which are usually overexpressed in patients with heart failure, and promote car-diac fibrosis in experimental models [2]. The latter hasbeen confirmed by clinical trials that show a reduction inmortality and hospitalization of patients with severe heartfailure in New York Heart Association class III–IV(NYHA III–IV) treated with spironolactone [3], or inpatients after a myocardial infarction complicated by areduced systolic function treated with eplerenone [4].Thus, it is reasonable to suppose that the use of aldoste-rone antagonists might also delay the progression of heartfailure in patients with mild failure symptoms (NYHA II).SummaryThe Eplerenone in Mild Patients Hospitalization and Sur-vival Study in Heart Failure (EMPHASIS-HF) trial [5]randomized 2,737 patients aged more than 55 years withNYHA II heart failure and an ejection fraction of not morethan 35%, to receive either eplerenone (up to 50 mg daily)or placebo, in addition to recommended therapy. The pri-mary outcome was a composite of death from cardiovas-cular causes or a first hospitalization for heart failure. Deathand hospitalization for any cause were secondary outcomes.The trial was planned to last 48 months, but it wasstopped prematurely, after a median follow-up period of21 months, because of an overwhelming benefit in theeplerenone group. The primary outcome occurred in 18.3%of patients in the eplerenone group as compared with25.9% in the placebo group (hazard ratio, 0.63, 95% con-fidence interval (CI), 0.54–0.74, P\0.001). A total of12.5% of patients receiving eplerenone and 15.5% of thosereceiving placebo died (hazard ratio, 0.76, 95% CI,0.62–0.93, P = 0.008); hospitalizations for heart failureand any other cause were also reduced with eplerenone.Among adverse events, only hyperkalemia showed a sig-nificant difference between the two groups: serum potas-sium level exceeding 5.5 mmol per litre occurred in 11.8%of patients in the eplerenone group and in 7.2% of those inthe placebo group (P\0.001). The estimated number ofpatients who would need to be treated to prevent one pri-mary outcome per year was 19 (95% CI 15–27), and theestimated number needed to treat to postpone one death peryear, was 51 (95% CI 32–180).Strength of the study– It addresses a relevant clinical issue (it’s the first trialconducted among the patients in class NYHA II).– Rationale of the study: there is a strong pathophysio-logic background for the utility of aldosterone antag-onists in heart failure patients, and the previous studyalready confirms this observation [3, 4];

Atrial fibrillation detection after cryptogenic stroke

Ischemic stroke is a significant cause of mortality and of serious long-term morbidity. It is estimated that cryptogenic stroke (stroke whose underlying causes remain unknown despite a complete work-up,) accounts for about 20–40 % of all ischemic events, one quarter of which tend to be recurrent [1]. Paroxysmal and persistent atrial fibrillation (AF) is a well-recognized cause of ischemic stroke, and the risk may be reduced with anticoagulation. However, only 5 % of patients are diagnosed to have AF after an ischemic stroke. Indeed the use of traditional monitoring techniques may not detect episodes of asymptomatic paroxysmal AF, which might underlie some apparently ‘‘cryptogenic’’ strokes. Therefore, the most effective duration of ECG monitoring has not been determined by current guidelines [2]. Nowadays, external and implanted loop recorders may allow identification of silent AF, thus increasing AF detection rate. However, the effectiveness of prolonged heart rhythm monitoring in patients with cryptogenic stroke is still unproved [3, 4].

Is dual RAAS blockade useful in diabetic nephropathy

Diabetic nephropathy is a progressive disease whose prevalence is increasing in developed countries (20–40 % of patients with diabetes mellitus) [1], with a significant impact on morbidity and mortality from chronic kidney disease (CKD), end stage renal disease (ESRD) and cardiovascular disease. This condition has also become a concern from the economic point of view, due to healthcare costs. Initiation and progression of diabetic kidney disease (DKD) are due to several different mechanisms, among which there is activation of the renin–angiotensin–aldosterone system (RAAS), with production of angiotensin II, a peptide with vasoactive, proinflammatory and pro-oxidant properties. Moreover, hypertension, which is often a comorbid condition in diabetic patients, is linked to diabetes bidirectionally because it can both be a concomitant cause and a consequence of kidney disease. Angiotensin receptor blockers (ARBs), angiotensin converting enzyme inhibitors (ACEIs) and, more recently, direct renin inhibitors (DRIs) have been demonstrated to reduce proteinuria and blood pressure, thus slowing progression of DKD, when used as monotherapy. On the basis of this evidence, some studies investigated if combined RAAS inhibition with an ARB and an ACEI (or an ARB/ACEI and a DRI) has a greater effect on disease severity and progression than either therapy alone. For example, two randomized trials, the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) [2] and the Aliskiren Trial in Type 2 Diabetes Using CardioRenal Endpoints (ALTITUDE) [3] show no benefit of combined RAAS therapy on cardiorenal endpoints, while a trend towards reduction in GFR, doubling of serum creatinine concentration, hyperkalemia, early dialysis initiation, higher risk of hypotension, stroke and death was observed. In April 2012, a safety communication warning by the US Food and Drug Administration (FDA) recommends the avoidance of the use of combination treatment with DRIs added to ACEIs or ARBs in patients with DKD or reduced GFR (\60 ml/min/1.73 m). However, the study population selection can be considered a limitation of these trials (for example, lack of patients with overt proteinuria and one-third of patients without hypertension in the ONTARGET) and evaluation of combined RAAS therapy in different subsets of patients is warranted.