Antonio L. Dans

RISK FACTORS FOR ISCHAEMIC AND INTRACEREBRAL HAEMORRHAGIC STROKE IN 22 COUNTRIES (THE INTERSTROKE STUDY): A CASE-CONTROL STUDY

BACKGROUNDnThe contribution of various risk factors to the burden of stroke worldwide is unknown, particularly in countries of low and middle income. We aimed to establish the association of known and emerging risk factors with stroke and its primary subtypes, assess the contribution of these risk factors to the burden of stroke, and explore the differences between risk factors for stroke and myocardial infarction.nnnMETHODSnWe undertook a standardised case-control study in 22 countries worldwide between March 1, 2007, and April 23, 2010. Cases were patients with acute first stroke (within 5 days of symptoms onset and 72 h of hospital admission). Controls had no history of stroke, and were matched with cases for age and sex. All participants completed a structured questionnaire and a physical examination, and most provided blood and urine samples. We calculated odds ratios (ORs) and population-attributable risks (PARs) for the association of all stroke, ischaemic stroke, and intracerebral haemorrhagic stroke with selected risk factors.nnnFINDINGSnIn the first 3000 cases (n=2337, 78%, with ischaemic stroke; n=663, 22%, with intracerebral haemorrhagic stroke) and 3000 controls, significant risk factors for all stroke were: history of hypertension (OR 2.64, 99% CI 2.26-3.08; PAR 34.6%, 99% CI 30.4-39.1); current smoking (2.09, 1.75-2.51; 18.9%, 15.3-23.1); waist-to-hip ratio (1.65, 1.36-1.99 for highest vs lowest tertile; 26.5%, 18.8-36.0); diet risk score (1.35, 1.11-1.64 for highest vs lowest tertile; 18.8%, 11.2-29.7); regular physical activity (0.69, 0.53-0.90; 28.5%, 14.5-48.5); diabetes mellitus (1.36, 1.10-1.68; 5.0%, 2.6-9.5); alcohol intake (1.51, 1.18-1.92 for more than 30 drinks per month or binge drinking; 3.8%, 0.9-14.4); psychosocial stress (1.30, 1.06-1.60; 4.6%, 2.1-9.6) and depression (1.35, 1.10-1.66; 5.2%, 2.7-9.8); cardiac causes (2.38, 1.77-3.20; 6.7%, 4.8-9.1); and ratio of apolipoproteins B to A1 (1.89, 1.49-2.40 for highest vs lowest tertile; 24.9%, 15.7-37.1). Collectively, these risk factors accounted for 88.1% (99% CI 82.3-92.2) of the PAR for all stroke. When an alternate definition of hypertension was used (history of hypertension or blood pressure >160/90 mm Hg), the combined PAR was 90.3% (85.3-93.7) for all stroke. These risk factors were all significant for ischaemic stroke, whereas hypertension, smoking, waist-to-hip ratio, diet, and alcohol intake were significant risk factors for intracerebral haemorrhagic stroke.nnnINTERPRETATIONnOur findings suggest that ten risk factors are associated with 90% of the risk of stroke. Targeted interventions that reduce blood pressure and smoking, and promote physical activity and a healthy diet, could substantially reduce the burden of stroke.nnnFUNDINGnCanadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Pfizer Cardiovascular Award, Merck, AstraZeneca, and Boehringer Ingelheim.

Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study

BACKGROUNDnStroke is a leading cause of death and disability, especially in low-income and middle-income countries. We sought to quantify the importance of potentially modifiable risk factors for stroke in different regions of the world, and in key populations and primary pathological subtypes of stroke.nnnMETHODSnWe completed a standardised international case-control study in 32 countries in Asia, America, Europe, Australia, the Middle East, and Africa. Cases were patients with acute first stroke (within 5 days of symptom onset and 72 h of hospital admission). Controls were hospital-based or community-based individuals with no history of stroke, and were matched with cases, recruited in a 1:1 ratio, for age and sex. All participants completed a clinical assessment and were requested to provide blood and urine samples. Odds ratios (OR) and their population attributable risks (PARs) were calculated, with 99% confidence intervals.nnnFINDINGSnBetween Jan 11, 2007, and Aug 8, 2015, 26u2008919 participants were recruited from 32 countries (13u2008447 cases [10u2008388 with ischaemic stroke and 3059 intracerebral haemorrhage] and 13u2008472 controls). Previous history of hypertension or blood pressure of 140/90 mm Hg or higher (OR 2·98, 99% CI 2·72-3·28; PAR 47·9%, 99% CI 45·1-50·6), regular physical activity (0·60, 0·52-0·70; 35·8%, 27·7-44·7), apolipoprotein (Apo)B/ApoA1 ratio (1·84, 1·65-2·06 for highest vs lowest tertile; 26·8%, 22·2-31·9 for top two tertiles vs lowest tertile), diet (0·60, 0·53-0·67 for highest vs lowest tertile of modified Alternative Healthy Eating Index [mAHEI]; 23·2%, 18·2-28·9 for lowest two tertiles vs highest tertile of mAHEI), waist-to-hip ratio (1·44, 1·27-1·64 for highest vs lowest tertile; 18·6%, 13·3-25·3 for top two tertiles vs lowest), psychosocial factors (2·20, 1·78-2·72; 17·4%, 13·1-22·6), current smoking (1·67, 1·49-1·87; 12·4%, 10·2-14·9), cardiac causes (3·17, 2·68-3·75; 9·1%, 8·0-10·2), alcohol consumption (2·09, 1·64-2·67 for high or heavy episodic intake vs never or former drinker; 5·8%, 3·4-9·7 for current alcohol drinker vs never or former drinker), and diabetes mellitus (1·16, 1·05-1·30; 3·9%, 1·9-7·6) were associated with all stroke. Collectively, these risk factors accounted for 90·7% of the PAR for all stroke worldwide (91·5% for ischaemic stroke, 87·1% for intracerebral haemorrhage), and were consistent across regions (ranging from 82·7% in Africa to 97·4% in southeast Asia), sex (90·6% in men and in women), and age groups (92·2% in patients aged ≤55 years, 90·0% in patients aged >55 years). We observed regional variations in the importance of individual risk factors, which were related to variations in the magnitude of ORs (rather than direction, which we observed for diet) and differences in prevalence of risk factors among regions. Hypertension was more associated with intracerebral haemorrhage than with ischaemic stroke, whereas current smoking, diabetes, apolipoproteins, and cardiac causes were more associated with ischaemic stroke (p<0·0001).nnnINTERPRETATIONnTen potentially modifiable risk factors are collectively associated with about 90% of the PAR of stroke in each major region of the world, among ethnic groups, in men and women, and in all ages. However, we found important regional variations in the relative importance of most individual risk factors for stroke, which could contribute to worldwide variations in frequency and case-mix of stroke. Our findings support developing both global and region-specific programmes to prevent stroke.nnnFUNDINGnCanadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Health Research Board Ireland, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland (Sweden), AstraZeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MSD, Chest, Heart and Stroke Scotland, and The Stroke Association, with support from The UK Stroke Research Network.

Tips for learners of evidence-based medicine: 1. Relative risk reduction, absolute risk reduction and number needed to treat

Physicians, patients and policy-makers are influenced not only by the results of studies but also by how authors present the results.[1][1],[2][2],[3][3],[4][4] Depending on which measures of effect authors choose, the impact of an intervention may appear very large or quite small, even though the

Estimating modifiable coronary heart disease risk in multiple regions of the world: the INTERHEART Modifiable Risk Score

AIMSnSummating risk factor burden is a useful approach in the assessment of cardiovascular risk among apparently healthy individuals. We aimed to derive and validate a new score for myocardial infarction (MI) risk using modifiable risk factors, derived from the INTERHEART case-control study (n = 19 470).nnnMETHODS AND RESULTSnMultiple logistic regression was used to create the INTERHEART Modifiable Risk Score (IHMRS). Internal validation was performed using split-sample methods. External validation was performed in an international prospective cohort study. A risk model including apolipoproteins, smoking, second-hand smoke exposure, hypertension, and diabetes was developed. Addition of further modifiable risk factors did not improve score discrimination in an external cohort. Split-sample validation studies showed an area under the receiver-operating characteristic (ROC) curve c-statistic of 0.71 [95% confidence interval (CI): 0.70, 0.72]. The IHMRS was positively associated with incident MI in a large cohort of people at low risk for cardiovascular disease [12% increase in MI risk (95% CI: 8, 16%) with a 1-point increase in score] and showed appropriate discrimination in this cohort (ROC c-statistic 0.69, 95% CI: 0.64, 0.74). Results were consistent across ethnic groups and geographic regions. A non-laboratory-based score is also supplied.nnnCONCLUSIONSnUsing multiple modifiable risk factors from the INTERHEART case-control study, we have developed and validated a simple score for MI risk which is applicable to an international population.

Digitalis for treatment of congestive heart failure in patients in sinus rhythm.

BACKGROUNDnDigitalis glycosides have been in clinical use in the treatment of congestive heart failure for more than 200 years. In recent years several trials have been conducted to address concerns about efficacy and toxicity. Although a systematic review of the literature was recently published, an update is required to include more current trials.nnnOBJECTIVESnTo examine the effectiveness of digitalis glycosides in treating congestive heart failure in patients with normal sinus rhythm. To examine the effect of digitalis in patients taking diuretics, angiotensin converting enzyme (ACE) inhibitors, and beta blockers; patients with varying severity and duration of disease; patients with prior exposure to digitalis vs. no prior exposure; and patients with diastolic vs. systolic dysfunction.nnnSEARCH STRATEGYnElectronic databases were searched between 1966 and 2000. Dissertation Abstracts and annual meeting abstracts of the American Heart Association, American College of Cardiology, and European Society of Cardiology were searched from 1996-2000. In addition, reference lists provided by the pharmaceutical industry (Glaxo Wellcome Inc.) were searched.nnnSELECTION CRITERIAnIncluded were randomized placebo-controlled trials of 20 or more adult patients of either sex with symptomatic congestive heart failure who were studied for seven weeks or more. Excluded were trials in which the prevalence of atrial fibrillation was 2% or greater, or in which any arrhythmia that might compromise cardiac function or any potentially reversible cause of heart failure such as acute ischemic heart disease or myocarditis was present.nnnDATA COLLECTION AND ANALYSISnArticles selected from the searches described above were reviewed by one of the coauthors, and validated by staff from the central office of the Heart Collaborative Review Group in Bristol, UK.nnnMAIN RESULTSnEleven articles meeting the defined criteria were identified, and major endpoints of mortality, hospitalization, and clinical status, based respectively upon 8, 4, and 10 of these selected studies, were recorded and analyzed. The data show that there is no difference in mortality between treatment and control groups, whereas digitalis therapy is associated with a lower rate of hospitalization and of clinical deterioration.nnnREVIEWERS CONCLUSIONSnThe literature indicates that digitalis has a useful role in the treatment of patients with congestive heart failure who are in normal sinus rhythm.

Vitamin B for treating peripheral neuropathy

BACKGROUNDnVitamin B is frequently used for treating peripheral neuropathy but its efficacy is not clear.nnnOBJECTIVESnThe objective of this review was to assess the effects of vitamin B for treating generalised peripheral neuropathy.nnnSEARCH STRATEGYnWe searched the Cochrane Neuromuscular Disease Group Trials Register (searched August 2005), MEDLINE (January 1966 to September 2005), EMBASE (January 1980 to September 2005), Philippine databases (searched September 2005) and reference lists of articles. We also contacted manufacturers and researchers in the field.nnnSELECTION CRITERIAnRandomised and quasi-randomised trials where vitamin B was compared with placebo or another treatment in generalised peripheral neuropathy.nnnDATA COLLECTION AND ANALYSISnTwo authors independently assessed trial quality and extracted data. We contacted study authors for additional information.nnnMAIN RESULTSnThirteen studies involving 741 participants with alcoholic or diabetic neuropathy were included. In the comparison of vitamin B with placebo, two small trials showed no significant short-term benefit in pain intensity while one of the trials showed a small significant benefit in vibration detection from oral benfotiamine, a derivative of thiamine. In the larger of two trials comparing different doses of vitamin B complex, there was some evidence that higher doses resulted in a significant short-term reduction in pain and improvement in paraesthesiae, in a composite outcome combining pain, temperature and vibration, and in a composite outcome combining pain, numbness and paraesthesiae. There was some evidence that vitamin B is less efficacious than alpha-lipoic acid, cilostazol or cytidine triphosphate in the short-term improvement of clinical and nerve conduction study outcomes but the trials were small. There were few minor adverse effects reported.nnnAUTHORS CONCLUSIONSnThere are only limited data in randomised trials testing the efficacy of vitamin B for treating peripheral neuropathy and the evidence is insufficient to determine whether vitamin B is beneficial or harmful. One small trial in alcoholic peripheral neuropathy reported slightly greater improvement in vibration perception threshold with oral benfotiamine for eight weeks than placebo. In another small study, a higher dose of oral vitamin B complex for four weeks was more efficacious than a lower dose in reducing symptoms and signs. Vitamin B administered by various routes for two to eight weeks was less efficacious than alpha-lipoic acid, cilostazol or cytidine triphosphate in short-term improvement of clinical and nerve conduction study outcomes. Vitamin B is generally well-tolerated.

Chelation therapy for atherosclerotic cardiovascular disease

BACKGROUNDnChelation therapy is being promoted and practiced all over the world as a form of alternative medicine in the treatment of atherosclerotic cardiovascular disease. It has been recommended as a safe, relatively inexpensive and non-surgical method of restoring blood flow in atherosclerotic vessels. At present the benefit of chelation therapy remains controversial at best.nnnOBJECTIVESnThe objective of this review is to assess the effects of ethylene diamine tetraacetic acid (EDTA) chelation therapy on clinical outcomes among patients with atherosclerotic cardiovascular disease.nnnSEARCH STRATEGYnThe reviewers searched the Cochrane Peripheral Vascular Diseases Group Trials Register, (last searched July 2002), the Cochrane Controlled Trials Register, (Cochrane Library Issue 2, 2002), MEDLINE and EMBASE for published articles and other relevant articles. Studies were also requested through correspondence with known Filipino practitioners of the procedure.nnnSELECTION CRITERIAnStudies were included if they were randomized controlled trials of EDTA chelation therapy versus placebo or no treatment in patients with atherosclerotic cardiovascular disease. Main outcome measures considered included either total or cause-specific mortality, non-fatal cardiovascular events, direct or indirect measurement of disease severity, subjective measures of improvement or adverse events.nnnDATA COLLECTION AND ANALYSISnTwo reviewers (MVV, FT) extracted data and assessed trial quality independently. Unresolved issues were considered by a third reviewer (ALD). Discrepancies were discussed until a consensus was reached. Authors were contacted for additional information.nnnMAIN RESULTSnA total of five studies was included in the review. Mortality, non-fatal events, and cerebrovascular events were not reported in any of the studies. Four of the studies, with a total recruitment rate of 250 participants, showed no significant difference in the following outcomes: direct or indirect measurement of disease severity and subjective measures of improvement. One of the studies, which included only 10 patients, was interrupted prematurely, because of an apparent treatment effect. However, relevant data were not available in the report and have been requested from the authors.nnnREVIEWERS CONCLUSIONSnAt present, there is insufficient evidence to decide on the effectiveness or ineffectiveness of chelation therapy in improving clinical outcomes of patients with atherosclerotic cardiovascular disease. This decision must be preceded by conducting randomized controlled trials that would include endpoints that show the effects of chelation therapy on longevity and quality of life among patients with atherosclerotic cardiovascular disease.

Dysglycaemia and the risk of acute myocardial infarction in multiple ethnic groups: an analysis of 15,780 patients from the INTERHEART study

Aims/hypothesisAlthough diabetes is an established risk factor for myocardial infarction (MI), disease control may vary. HbA1c is a reliable index of ambient glucose levels and may provide more information on MI risk than diabetes status.MethodsThe relationship between HbA1c levels in MI patients and controls who participated in the 52 country INTERHEART study was analysed.ResultsIn 15,780 participants with a HbA1c value (1,993 of whom had diabetes), the mean (SD) levels for HbA1c were 6.15% (1.10) in the 6,761 MI patients and 5.85% (0.80) in the control participants. After adjustment for age, sex and nine major MI risk factors (including diabetes), higher HbA1c fifths above the lowest fifth (HbA1c <5.4%) were associated with progressively higher OR of MI, with OR for the highest HbA1c fifth (≥6.12%) being 1.55 (95% CI 1.37–1.75). When analysed as a continuous variable after adjustment for the same factors, every 1% higher HbA1c value was associated with 19% (95% CI 14–23) higher odds of MI, while every 0.5% higher HbA1c was associated with 9% higher odds of MI (95% CI 7–11). Concordant relationships were noted across subgroups, with a higher OR noted in younger people, patients without diabetes or hypertension, and those from some regions and ethnicities.Conclusions/interpretationThe HbA1c value provides more information on MI odds than self-reported diabetes status or many other established risk factors. Every 1% increment independently predicts a 19% higher odds of MI after accounting for other MI risk factors including diabetes.

The Brugada type 1 electrocardiographic pattern is common among Filipinos.

OBJECTIVEnTo measure the prevalence of the Brugada type 1 ECG pattern in the general population in the Philippines. STUDY SETTING AND DESIGN: Sudden unexplained death syndrome is rare in the West but is common among Southeast Asians. Ventricular fibrillation is the terminal event. The Brugada type 1 electrocardiographic (ECG) pattern with J point and coved ST elevation in right precordial leads, is a marker for sudden unexplained death syndrome. Its prevalence in the general population is unknown. A cross-sectional nationwide survey was performed in the Philippines in 2003 using a stratified multistage sampling design covering all the regions and provinces in the country. ECGs were performed in all adults surveyed. The prevalences of the Brugada type 1 ECG pattern (coved type) and any type Brugada ECG pattern were determined.nnnRESULTSnThe Brugada type 1 (coved) ECG pattern in the general population in the Philippines was found in 0.2% (95% Confidence Interval [CI] 0.03%-0.36%) of the population. Among males the prevalence was 0.3% (+/-0.1). The prevalence of any type Brugada ECG was 2% (95% CI 1.5%-2.6%).nnnCONCLUSIONnThe Brugada ECG pattern is common among Filipinos. There is a need to determine the risk of sudden death among individuals with this marker in the general population.

Digitalis for treatment of heart failure in patients in sinus rhythm

BACKGROUNDnDigitalis glycosides have been in clinical use for the treatment of heart failure (HF) for longer than 200 years. In recent years, several trials have been conducted to address concerns about their efficacy and toxicity.nnnOBJECTIVESnTo examine the effectiveness of digitalis glycosides in treating HF in patients with normal sinus rhythm. To examine the effects of digitalis in patients taking diuretics and angiotensin-converting enzyme inhibitors; in patients with varying severity and duration of disease; in patients with prior exposure to digitalis versus no prior exposure; and in patients with HF due to systolic dysfunction versus HF with preserved ejection fraction.nnnSEARCH METHODSnSearches on the following databases were updated in May 2013: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Dissertation Abstracts. Annual meeting abstracts of the American Heart Association, the American College of Cardiology, and the European Society of Cardiology were searched from 1996 to March 2013. In addition, reference lists provided by the pharmaceutical industry (GlaxoSmithKline and Covis Pharma) were searched.nnnSELECTION CRITERIAnIncluded were randomized placebo-controlled trials of 20 or more adult participants of either sex with symptomatic HF who were studied for seven weeks or longer. Excluded were trials in which the prevalence of atrial fibrillation was 2% or greater, or in which any arrhythmia that might compromise cardiac function or any potentially reversible cause of HF such as acute ischemic heart disease or myocarditis was present.nnnDATA COLLECTION AND ANALYSISnArticles selected from the searches described above were evaluated in a joint effort of the review authors. The staff of the Cochrane Heart Group ran searches on the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE.nnnMAIN RESULTSnNo new studies were identified in the updated searches. Thirteen studies (7896 participants) are included, and major endpoints of mortality, hospitalization, and clinical status, based respectively on 8, 4, and 12 of these selected studies, were recorded and analyzed. The data show no evidence of a difference in mortality between treatment and control groups, whereas digitalis therapy is associated with lower rates of both hospitalization and clinical deterioration. The largest study, in which most participants were taking angiotensin-converting enzyme inhibitors, showed a significant rise in other cardiac deaths, possibly due to arrhythmias. However collectively, these findings were based on studies done before beta-blockers, as well as angiotensin receptor blockers and aldosterone antagonists, became widely used to treat HF.nnnAUTHORS CONCLUSIONSnThe literature indicates that digitalis may have a useful role in the treatment of patients with HF who are in normal sinus rhythm. New trials are needed to elucidate the importance of the dosage of digitalis and its usefulness in the era of beta-blockers and other agents shown to be effective in treating HF.