Followers

Wednesday, January 30, 2008

Increased Bleeding Risk With Concurrent Use of Selective Serotonin Reuptake Inhibitors and Coumarins

Increased Bleeding Risk With Concurrent Use of Selective Serotonin Reuptake Inhibitors and Coumarins

Tom Schalekamp, PharmD, PhD; J H. Klungel, PharmD, PhD; Patrick C. Souverein, PhD; Anthonius de Boer, MD, PhD

Arch Intern Med. 2008;168(2):180-185.

Background Treatment with vitamin K antagonists (coumarins) is associated with an increased risk of bleeding. Because use of selective serotonin reuptake inhibitors (SSRIs) is also associated with an increased risk of bleeding, we assessed the odds ratio (OR) of abnormal bleeding associated with SSRI use in users of the coumarins acenocoumarol or phenprocoumon and compared this with the OR of bleeding as a result of use of nonsteroidal anti-inflammatory drugs.
Methods We used data from a Dutch linkage system including pharmacy and linked hospitalization records for approximately 2 million subjects to conduct a case-control study in a cohort of new users of coumarins. Cases were patients who were hospitalized having a primary diagnosis of abnormal major bleeding while taking a coumarin and were matched with up to 4 control subjects. Conditional logistic regression analysis was used to determine ORs and 95% confidence intervals (CIs) for the risk of hospitalization because of abnormal bleeding associated with concurrent use of SSRIs or nonsteroidal anti-inflammatory drugs.

Results We identified 1848 case patients with abnormal bleeding. Users of SSRIs were at significantly increased risk of hospitalization because of nongastrointestinal tract bleeding (hereafter referred to as "nongastrointestinal bleeding") (adjusted OR, 1.7; 95% CI, 1.1-2.5) but not because of gastrointestinal tract bleeding (hereafter referred to as "gastrointestinal bleeding") (adjusted OR, 0.8; 95% CI, 0.4-1.5). Users of nonsteroidal anti-inflammatory drugs had a similar increased risk of nongastrointestinal bleeding (adjusted OR, 1.7; 95% CI, 1.3-2.2), whereas the risk of gastrointestinal bleeding was higher (adjusted OR, 4.6; 95% CI, 3.3-6.5).

Conclusion In users of coumarins, SSRI usage was associated with increased risk of hospitalization because of nongastrointestinal bleeding but not because of gastrointestinal bleeding.

Tuesday, January 29, 2008

Ventricular Arrhythmias During Clinical Treadmill Testing and Prognos

Ventricular Arrhythmias During Clinical Treadmill Testing and Prognosis


Frederick E. Dewey, BA; John R. Kapoor, MD, PhD; Ryan S. Williams, MD; Michael J. Lipinski, MD; Euan A. Ashley, MRCP, DPhil; David Hadley, PhD; Jonathan Myers, PhD; Victor F. Froelicher, MD

Arch Intern Med. 2008;168(2):225-234.

Background Although exercise-associated ventricular arrhythmias are frequently observed during exercise testing, their prognostic significance remains uncertain. Therefore, we aimed to evaluate the clinical correlates and prognostic significance of exercise-associated premature ventricular complexes (PVCs) during and after exercise testing.

Methods We studied 1847 heart failure–free patients who underwent clinical treadmill testing between March 13, 1997, and January 15, 2004, in the Veterans Affairs Palo Alto Health Care System. Logistic regression was used to evaluate the clinical and exercise test associations of exercise and recovery PVCs. Propensity score–adjusted Cox survival analyses were used to evaluate the prognostic significance of exercise-associated PVCs.

Results Of the 1847 subjects, 850 (46.0%) developed exercise PVCs (median rate, 0.43 per minute) and 620 (33.6%) had recovery PVCs (median rate, 0.60 per minute). Resting PVCs, age, and systolic blood pressure were key predictors of both exercise and recovery PVCs. Whereas exercise PVCs were related to the heart rate increase with exercise, recovery PVCs were related to coronary disease (previous myocardial infarction, coronary revascularization procedure, or pathological Q waves on resting electrocardiogram) and ST-segment depression. During a 5.4-year mean follow-up, 161 subjects (8.7%) died, and 53 of these deaths (32.9%) were due to cardiovascular causes. Recovery PVCs, but not exercise PVCs, were associated with 71% to 96% greater propensity-adjusted mortality rates (hazard ratio, 1.96 [95% confidence interval, 1.31-2.91] for infrequent PVCs; hazard ratio, 1.71 [95% confidence interval, 1.07-2.73] for frequent PVCs compared with subjects without PVCs), and occurrence of recovery PVCs reclassified 33.2% of subjects with intermediate-risk Duke Treadmill Scores into higher-risk subgroups.

Conclusion In our heart failure–free population, recovery PVCs were associated with increased mortality and augmented established risk markers.

Diuretics Most Effective Blood Pressure Medication For People With Metabolic Syndrome


Commentaries:

The ALLHAT study originally reported in 2002 that diuretics were the most beneficial of the drug classes studied for treating high blood pressure and for protecting against adverse cardiovascular outcomes. The study compare a diuretic (chlorthalidone) with three classes of medications to treat high blood pressure: a calcium-channel blocker (amlodipine besylate), an alpha-blocker (doxazosin mesylate), and an angiotensin-converting enzyme (ACE) inhibitor (lisinopril).

Diuretic-based treatment was more protective against heart failure and also against overall cardiovascular disease (coronary heart disease, stroke, heart failure, or peripheral arterial disease combined) when compared with the ACE-inhibitor and alpha-blocker-based treatments.
Diuretic-based treatment was more protective against heart failure when compared with the calcium channel blocker-based treatment.

Clinical Outcomes by Race in Hypertensive Patients With and Without the Metabolic Syndrome Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

Jackson T. Wright Jr, MD, PhD; Sonja Harris-Haywood, MD; Sara Pressel, MS; Joshua Barzilay, MD; Charles Baimbridge, MS; Charles J. Bareis, MD; Jan N. Basile, MD; Henry R. Black, MD; Richard Dart, MD; Alok K. Gupta, MD; Bruce P. Hamilton, MD; Paula T. Einhorn, MD, MS; L. Julian Haywood, MD; Syed Z. A. Jafri, MD; Gail T. Louis, RN, BA; Paul K. Whelton, MD, MSc; Cranford L. Scott, MD; Debra L. Simmons, MD; Carol Stanford, MD; Barry R. Davis, MD, PhD

Arch Intern Med. 2008;168(2):207-217.

Background Antihypertensive drugs with favorable metabolic effects are advocated for first-line therapy in hypertensive patients with metabolic/cardiometabolic syndrome (MetS). We compared outcomes by race in hypertensive individuals with and without MetS treated with a thiazide-type diuretic (chlorthalidone), a calcium channel blocker (amlodipine besylate), an -blocker (doxazosin mesylate), or an angiotensin-converting enzyme inhibitor (lisinopril).

Methods A subgroup analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind hypertension treatment trial of 42 418 participants. We defined MetS as hypertension plus at least 2 of the following: fasting serum glucose level of at least 100 mg/dL, body mass index (calculated as weight in kilograms divided by height in meters squared) of at least 30, fasting triglyceride levels of at least 150 mg/dL, and high-density lipoprotein cholesterol levels of less than 40 mg/dL in men or less than 50 mg/dL in women.

Results Significantly higher rates of heart failure were consistent across all treatment comparisons in those with MetS. Relative risks (RRs) were 1.50 (95% confidence interval, 1.18-1.90), 1.49 (1.17-1.90), and 1.88 (1.42-2.47) in black participants and 1.25 (1.06-1.47), 1.20 (1.01-1.41), and 1.82 (1.51-2.19) in nonblack participants for amlodipine, lisinopril, and doxazosin comparisons with chlorthalidone, respectively. Higher rates for combined cardiovascular disease were observed with lisinopril-chlorthalidone (RRs, 1.24 [1.09-1.40] and 1.10 [1.02-1.19], respectively) and doxazosin-chlorthalidone comparisons (RRs, 1.37 [1.19-1.58] and 1.18 [1.08-1.30], respectively) in black and nonblack participants with MetS. Higher rates of stroke were seen in black participants only (RR, 1.37 [1.07-1.76] for the lisinopril-chlorthalidone comparison, and RR, 1.49 [1.09-2.03] for the doxazosin-chlorthalidone comparison). Black patients with MetS also had higher rates of end-stage renal disease (RR, 1.70 [1.13-2.55]) with lisinopril compared with chlorthalidone.

Conclusions The ALLHAT findings fail to support the preference for calcium channel blockers, -blockers, or angiotensin-converting enzyme inhibitors compared with thiazide-type diuretics in patients with the MetS, despite their more favorable metabolic profiles. This was particularly true for black participants.

Monday, January 28, 2008

ACE inhibitor prevents cardiac rupture after acute MI

Causes of death in patients with acute myocardial infarction treated with angiotensin-converting enzyme inhibitors: Findings from the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto (GISSI)–3 trial

American Heart Journal
Volume 155, Issue 2, Pages 388-394 (February 2008)

Giovanni Pedrazzini, MD, Eugenio Santoro, MS, Roberto Latini, MD, Laurie Fromm, PharmD, Maria Grazia Franzosi, BiolScD, Tiziano Mocetti, MD, Lidia Staszewsky, MD, Simona Barlera, MS, Gianni Tognoni, MD, Aldo P. Maggioni, MD


Background


The causes of death occurring in clinical trials of myocardial infarction (MI) are scarcely reported in the literature. The present analysis is aimed to describe the inhospital causes of death in patients with acute MI stratified to angiotensin converting enzyme (ACE) inhibitor treatment/no treatment, as described in the GISSI-3 trial. Furthermore, the 5-year survival analysis of GISSI-3 patients is reported.


Methods and Results
An independent committee assigned the definition of causes of death of GISSI-3 based on clinical and/or anatomical data. Univariate and multivariable analyses were performed to identify the predictors of early and late deaths. Kaplan-Meier mortality curves were used to describe the effects of ACE-I treatment on mortality on a median follow-up period of 56 months.
Patients receiving lisinopril had fewer inhospital cardiac deaths than patients allocated to the no-lisinopril group (4.7% vs 5.3%, P = .052), corresponding to a 12% relative risk reduction. The risk of dying from cardiac rupture was reduced by 39% by lisinopril treatment. The improvement in survival associated with the lisinopril treatment was mainly due to a reduction in cardiac rupture, electromechanical dissociation, and pump failure occurring early (within 4 days) from the onset of MI symptoms.

The beneficial effects of lisinopril observed at 6 weeks (8 fewer deaths per 1000 treated patients) were maintained up to nearly 5 years (10 fewer deaths per 1000).


Conclusions
Early administration of ACE inhibitors in unselected patients with acute MI should be considered standard therapy to reduce early deaths, specifically those due to cardiac rupture. The early beneficial effect persisted up to nearly 5 years.

Digitalis: a dangerous drug in atrial fibrillation? An analysis of the SPORTIF III and V data

Commentaries:

In this study patients were not randomized to digitalis use.


Digitalis: a dangerous drug in atrial fibrillation? An analysis of the SPORTIF III and V data

Heart 2008; 94: 191-196
Knut Gjesdal (University of Oslo, Norway) and colleagues

ABSTRACT

Objective: In heart failure, digitalis increases exercise capacity and reduces morbidity, but has no effect on survival. This raises the suspicion that the inotropic benefits of digitalis may be counteracted by serious adverse effects. Patients with atrial fibrillation (AF) were studied to clarify this.

Design: In the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF) III and V studies, 7329 patients with AF at moderate-to-high risk were randomised to preventive treatment of thromboembolism, either with warfarin or the oral direct thrombin inhibitor ximelagatran. The survival of users and non-users of digitalis was investigated.

Results: At baseline, 53.4% of the study population used digitalis, and these patients had a higher mortality than non-users (255/3911 (6.5%) vs 141/3418 (4.1%), p<0.001; hazard ratio (HR) = 1.58 (95% CI 1.29 to 1.94)). Digitalis users also had more baseline risk factors. After multivariate risk factor adjustment, the increased mortality persisted (p<0.001; HR = 1.53 (95% CI 1.22 to 1.92 vs 1.23 to 1.92)).

Conclusions: The results suggest that digitalis, like other inotropic drugs, may increase mortality. This may be concealed in heart failure, but be revealed in patients with AF, who need the rate-reducing effect of digitalis, but do not benefit much from an increased inotropy. Cautious interpretation of the data is mandatory since the patients were not randomised with respect to digitalis use.

Similar outcome after thrombolysis or primary angioplasty in STEMI

Comparison of Left Ventricular Ejection Fraction and Inducible Ventricular Tachycardia in ST-Elevation Myocardial Infarction Treated by Primary Angioplasty Versus Thrombolysis

American Journal of Cardiology

Volume 101, Issue 2, Pages 153-157 (15 January 2008)


James J.H. Chong, MDa, Anand N. Ganesan, MD, PhD, Vicki Eippera, Pramesh Kovoor, MD, PhD


Electrophysiologic studies predict the risk for sudden death after myocardial infarction (MI). Although primary angioplasty has become the preferred method of treatment for ST-elevation MI, intravenous thrombolysis remains the first-line treatment in 30% to 70% of cases worldwide. Rates of ventricular tachyarrhythmias may vary according to type of reperfusion treatment. This study was undertaken to examine the hypothesis that the left ventricular ejection fraction (LVEF) and rates of inducible ventricular tachycardia may be more favorable in treatment with primary angioplasty rather than thrombolysis. Consecutive patients receiving primary angioplasty (n = 225) or thrombolysis (n = 195) for ST-elevation MI were included. The mean LVEF was 48 ± 12% for the primary angioplasty group and 46 ± 13% for the thrombolysis group (p = 0.30). The proportion of patients with LVEFs <40% was 30% in the primary angioplasty group and 30% in the thrombolysis group (p = 0.98). Patients with LVEFs <40% underwent electrophysiologic studies. Ventricular tachycardia was inducible in 23 of 66 primary angioplasty patients (34.8%) compared with 21 of 55 (38.1%) thrombolysis patients (p = 0.69). Implantable cardiac defibrillators were inserted in 30 patients, of whom 8 (27%) had appropriate device activations. The mean time from MI to first spontaneous activation was 387 ± 458 days.

In conclusion, patients treated with thrombolysis or primary angioplasty for ST-elevation MIs had similar resultant LVEFs and rates of inducible ventricular tachycardia. There was a surprisingly high rate of spontaneous defibrillator activations, often occurring late after MI.

Thursday, January 24, 2008

Drug-Eluting Stents vs. Coronary-Artery Bypass Grafting in Multivessel Coronary Disease



Drug-Eluting Stents vs. Coronary-Artery Bypass Grafting in Multivessel Coronary Disease

New England Journal of Medicine, January 24, 2008.

Edward L. Hannan, Ph.D., Chuntao Wu, M.D., Ph.D., Gary Walford, M.D., Alfred T. Culliford, M.D., Jeffrey P. Gold, M.D., Craig R. Smith, M.D., Robert S.D. Higgins, M.D., Russell E. Carlson, M.D., and Robert H. Jones, M.D.


ABSTRACT

Background
Numerous studies have compared the outcomes of two competing interventions for multivessel coronary artery disease: coronary-artery bypass grafting (CABG) and coronary stenting. However, little information has become available since the introduction of drug-eluting stents.

Methods We identified patients with multivessel disease who received drug-eluting stents or underwent CABG in New York State between October 1, 2003, and December 31, 2004, and we compared adverse outcomes (death, death or myocardial infarction, or repeat revascularization) through December 31, 2005, after adjustment for differences in baseline risk factors among the patients.

Results In comparison with treatment with a drug-eluting stent, CABG was associated with lower 18-month rates of death and of death or myocardial infarction both for patients with three-vessel disease and for patients with two-vessel disease. Among patients with three-vessel disease who underwent CABG, as compared with those who received a stent, the adjusted hazard ratio for death was 0.80 (95% confidence interval [CI], 0.65 to 0.97) and the adjusted survival rate was 94.0% versus 92.7% (P=0.03); the adjusted hazard ratio for death or myocardial infarction was 0.75 (95% CI, 0.63 to 0.89) and the adjusted rate of survival free from myocardial infarction was 92.1% versus 89.7% (P<0.001). Among patients with two-vessel disease who underwent CABG, as compared with those who received a stent, the adjusted hazard ratio for death was 0.71 (95% CI, 0.57 to 0.89) and the adjusted survival rate was 96.0% versus 94.6% (P=0.003); the adjusted hazard ratio for death or myocardial infarction was 0.71 (95% CI, 0.59 to 0.87) and the adjusted rate of survival free from myocardial infarction was 94.5% versus 92.5% (P<0.001). Patients undergoing CABG also had lower rates of repeat revascularization.

Conclusions For patients with multivessel disease, CABG continues to be associated with lower mortality rates than does treatment with drug-eluting stents and is also associated with lower rates of death or myocardial infarction and repeat revascularization.

Wednesday, January 23, 2008

New Drugs for the Treatment of Diabetes Mellitus: Part I: Thiazolidinediones and Their Evolving Cardiovascular Implications

Merck Sharp & Dohme


Circulation:Volume 117(3)22 January 2008pp 440-449

New Drugs for the Treatment of Diabetes Mellitus: Part I: Thiazolidinediones and Their Evolving Cardiovascular Implications


Conclusions

In summary, thiazolidinedione effects on the cardiovascular system extend beyond their impact on glucose metabolism, yielding much interest in their effect on CVD risk, with numerous trials underway. Both rosiglitazone and pioglitazone are similarly associated with peripheral edema and, much less commonly, HF, warranting continued caution for their use in HF patients according to their product labels, Food and Drug Administration guidance, and AHA/American Diabetes Association recommendations.57 Pioglitazone has demonstrated favorable trends for CVD risk reduction in the PROactive study, the largest CVD outcomes trial of glucose-modifying therapy completed to date. The safety signal associated with potential increased CVD risk associated with rosiglitazone warrants caution for its use, but the paucity of evaluable data in this context justifies continued clinical trial assessment with judicious safety monitoring of ongoing clinical trials. Until such additional safety and efficacy data are available, in the context of what may now appear to be safer alternatives to rosiglitazone available, including but not limited to pioglitazone, its routine use in the treatment of hyperglycemia in patients with T2DM at increased CVD risk cannot be recommended.

Adjustable Gastric Banding and Conventional Therapy for Type 2 Diabetes A Randomized Controlled Trial

Adjustable Gastric Banding and Conventional Therapy for Type 2 Diabetes A Randomized Controlled Trial

John B. Dixon, MBBS, PhD; Paul E. O’Brien, MD; Julie Playfair, RN; Leon Chapman, MBBS; Linda M. Schachter, MBBS, PhD; Stewart Skinner, MBBS, PhD; Joseph Proietto, MBBS, PhD; Michael Bailey, PhD, MSc(stats); Margaret Anderson, BHealthMan

JAMA. 2008;299(3):316-323.

Context Observational studies suggest that surgically induced loss of weight may be effective therapy for type 2 diabetes.

Objective To determine if surgically induced weight loss results in better glycemic control and less need for diabetes medications than conventional approaches to weight loss and diabetes control.

Design, Setting, and Participants Unblinded randomized controlled trial conducted from December 2002 through December 2006 at the University Obesity Research Center in Australia, with general community recruitment to established treatment programs. Participants were 60 obese patients (BMI >30 and <40) with recently diagnosed (<2 years) type 2 diabetes.
Interventions Conventional diabetes therapy with a focus on weight loss by lifestyle change vs laparoscopic adjustable gastric banding with conventional diabetes care.

Main Outcome Measures Remission of type 2 diabetes (fasting glucose level <126 mg/dL [7.0 mmol/L] and glycated hemoglobin [HbA1c] value <6.2% while taking no glycemic therapy). Secondary measures included weight and components of the metabolic syndrome. Analysis was by intention-to-treat.

Results Of the 60 patients enrolled, 55 (92%) completed the 2-year follow-up. Remission of type 2 diabetes was achieved by 22 (73%) in the surgical group and 4 (13%) in the conventional-therapy group. Relative risk of remission for the surgical group was 5.5 (95% confidence interval, 2.2-14.0). Surgical and conventional-therapy groups lost a mean (SD) of 20.7% (8.6%) and 1.7% (5.2%) of weight, respectively, at 2 years (P < .001). Remission of type 2 diabetes was related to weight loss (R2 = 0.46, P < .001) and lower baseline HbA1c levels (combined R2 = 0.52, P < .001). There were no serious complications in either group.

Conclusions Participants randomized to surgical therapy were more likely to achieve remission of type 2 diabetes through greater weight loss. These results need to be confirmed in a larger, more diverse population and have long-term efficacy assessed.

Hawthorn extract for treating chronic heart failure

Commentaries:

The Cochrane analysis did not include results from SPICE, a large placebo-controlled trial presented at a major cardiology meeting last year that found equivocal benefits at best for hawthorn extract.


Hawthorn extract for treating chronic heart failure


Cochrane Database of Systematic Reviews

This version first published online: 23 January 2008 in Issue 1, 2008


Abstract

Background

Hawthorn extract is advocated as an oral treatment option for chronic heart failure. Also, the German Commission E approved the use of extracts of hawthorn leaf with flower in patients suffering from heart failure graded stage II according to the New York Heart Association.


Objectives

To assess the benefits and harms as reported in double-blind randomised clinical trials of hawthorn extract compared with placebo for treating patients with chronic heart failure.

Selection criteria

To be included, studies were required to state that they were randomised, double-blind, and placebo controlled, and used hawthorn leaf and flower extract monopreparations.

Data collection and analysis

Two reviewers independently performed the selection of studies, data extraction, and assessment of methodological quality. Data were entered into RevMan 4.2 software. Results from continuous data were reported as weighted mean difference (WMD) with 95% confidence interval (CI). Where data were suitable for combining, pooled results were calculated.

Main results

Fourteen trials met all inclusion criteria and were included in this review. In most of the studies, hawthorn was used as an adjunct to conventional treatment. Ten trials including 855 patients with chronic heart failure (New York Heart Association classes I to III) provided data that were suitable for meta-analysis. For the physiologic outcome of maximal workload, treatment with hawthorn extract was more beneficial than placebo (WMD (Watt) 5.35, 95% CI 0.71 to 10.00, P < 0.02, n = 380). Exercise tolerance were significantly increased by hawthorn extract (WMD (Watt x min) 122.76, 95% CI 32.74 to 212.78, n = 98). The pressure-heart rate product, an index of cardiac oxygen consumption, also showed a beneficial decrease with hawthorn treatment (WMD (mmHg/min) -19.22, 95% CI -30.46 to -7.98, n = 264). Symptoms such as shortness of breath and fatigue improved significantly with hawthorn treatment as compared with placebo (WMD -5.47, 95% CI -8.68 to -2.26, n = 239). No data on relevant mortality and morbidity such as cardiac events were reported, apart from one trial, which reported deaths (three in active, one in control) without providing further details. Reported adverse events were infrequent, mild, and transient; they included nausea, dizziness, and cardiac and gastrointestinal complaints.

Authors' conclusions

These results suggest that there is a significant benefit in symptom control and physiologic outcomes from hawthorn extract as an adjunctive treatment for chronic heart failure.

Plain language summary

Hawthorn extract (made from the dried leaves, flowers and fruits of the hawthorn bush) may be used as an oral treatment option for chronic heart failure. In this review, 14 double-blind, placebo controlled randomised clinical trials (RCTs) were found. They did not all measure the same outcomes and several did not explain what other heart failure treatments patients were receiving. Those trials that could be included in a meta-analysis showed improvements in heart failure symptoms and in the function of the heart. The results, therefore, are suggestive of a benefit from hawthorn extract used in addition to conventional treatments for chronic heart failure.

Work stress and coronary heart disease: what are the mechanisms?

Work stress and coronary heart disease: what are the mechanisms?

European Heart Journal Advance Access published online on January 23, 2008

Aims: To determine the biological and behavioural factors linking work stress with coronary heart disease (CHD).

Methods and results: A total of 10 308 London-based male and female civil servants aged 35–55 at phase 1 (1985–88) of the Whitehall II study were studied. Exposures included work stress (assessed at phases 1 and 2), and outcomes included behavioural risk factors (phase 3), the metabolic syndrome (phase 3), heart rate variability, morning rise in cortisol (phase 7), and incident CHD (phases 2–7) on the basis of CHD death, non-fatal myocardial infarction, or definite angina. Chronic work stress was associated with CHD and this association was stronger among participants aged under 50 (RR 1.68, 95% CI 1.17–2.42). There were similar associations between work stress and low physical activity, poor diet, the metabolic syndrome, its components, and lower heart rate variability. Cross-sectionally, work stress was associated with a higher morning rise in cortisol. Around 32% of the effect of work stress on CHD was attributable to its effect on health behaviours and the metabolic syndrome.

Conclusion: Work stress may be an important determinant of CHD among working-age populations, which is mediated through indirect effects on health behaviours and direct effects on neuroendocrine stress pathways.

Tuesday, January 22, 2008



A 53 year-old man was referred for evaluation because his brother suffered a cardiac arrest at the age of 42. His EKG is above.Diagnosis? Work-up? Recommendations?
Reference:

Zetia - Cholesterol - Drug Trials - Heart - Medicine and Health - New York Times

Jan 22, 2008

Columnist highlights Vytorin's ability to reduce cholesterol. (New York Times)


Zetia - Cholesterol - Drug Trials - Heart - Medicine and Health - New York Times

Zetia - Cholesterol - Drug Trials - Heart - Medicine and Health - New York Times

Jan 22, 2008

Columnist highlights Vytorin's ability to reduce cholesterol. (New York Times)


Zetia - Cholesterol - Drug Trials - Heart - Medicine and Health - New York Times

Zetia - Cholesterol - Drug Trials - Heart - Medicine and Health - New York Times

Jan 22, 2008

Columnist highlights Vytorin's ability to reduce cholesterol. (New York Times)


Zetia - Cholesterol - Drug Trials - Heart - Medicine and Health - New York Times

Screening for Carotid Artery Stenosis: An Update of the Evidence for the U.S. Preventive Services Task Force

Screening for Carotid Artery Stenosis: An Update of the Evidence for the U.S. Preventive Services Task Force

American College of Cardiology
Journal Scan

Ann Intern Med. 2007 Dec 18;147(12):860-70.


Perspective: The following are 10 points to remember about screening for carotid artery stenosis.

1. Cerebrovascular disease is the third leading cause of death in the United States and ~500,000 people experience their first stroke annually.

2. There has been a 70% decline in mortality from cerebrovascular disease in the United States since 1950. This is primarily related to reduction in smoking and better management of hypertension.

3. Almost 88% of strokes are ischemic in nature, and of these, 20% are due to large artery stenosis.

4. A stenosis severity of greater than 50%-60% is considered clinically important because these lesions have been associated with an increased risk of stroke.

5. The prevalence of clinically important asymptomatic carotid artery stenosis is estimated to be <1% in the general primary care population and ~1% in the population ≥65 years of age.

6. Carotid endarterectomy (CEA) is highly effective at reducing risk of subsequent stroke in patients who have had a transient ischemic attack or a minor stroke and have an ipsilateral severe carotid artery stenosis.

7. Duplex ultrasonography has high sensitivity and specificity (over 90%) for detecting severe carotid artery stenosis. Both computed tomography angiography and magnetic resonance angiography have similar accuracy for detection of severe asymptomatic carotid artery stenosis.

8. In selected patients undergoing CEA for severe asymptomatic carotid artery stenosis by select surgeons, the 5-year risk of stroke was reduced from 11.8 % to 6.4% with surgery. The perioperative risk of death or stroke was 3.1%. About half of the strokes prevented by surgery are disabling.

9. The outcome of patients undergoing CEA outside of clinical trials is variable with a stroke and death rate that has ranged from 2.3% to 3.7%, although rates as high as 6% have been reported. The incidence of periprocedural myocardial infarction varies from 0.7% to 1.1% in most published series, and may be higher because routine screening for asymptomatic myocardial infarction is uncommon.

10. No study has evaluated the benefit of screening for asymptomatic carotid artery stenosis. Assuming a prevalence of 1% in people over 65 years of age and a sensitivity of 94% and a specificity of 92% for ultrasonic screening and a perioperative death or stroke rate of 3.1%, 4,348 people would need to be screened to prevent one stroke, and 8,696 people would need to be screened to prevent one disabling stroke.

Routine screening for carotid artery stenosis is currently not recommended. Hitinder S. Gurm, M.B.B.S., F.A.C.C.

Initial Aspirin Dose and Outcome Among ST-Elevation Myocardial Infarction Patients Treated With Fibrinolytic Therapy

Commentaries:
Increased dose increased bleeding. What´s the mre convenient dose of Aspirin?

Initial Aspirin Dose and Outcome Among ST-Elevation Myocardial Infarction Patients Treated With Fibrinolytic Therapy

Circulation
Volume 117, Issue 2; January 15, 2008

Jeffrey S. Berger, MD, MS; Amanda Stebbins, MS; Christopher B. Granger, MD; Eric M. Ohman, MD; Paul W. Armstrong, MD; Frans Van de Werf, MD, PhD; Harvey D. White, DSc; R. John Simes, MD; Robert A. Harrington, MD; Robert M. Califf, MD; Eric D. Peterson, MD, MPH

BackgroundAlthough treatment with immediate aspirin reduces morbidity and mortality in ST-elevation myocardial infarction, the optimal dose is unclear. We therefore compared the acute mortality and bleeding risks associated with the initial use of 162 versus 325 mg aspirin in fibrinolytic-treated ST-elevation myocardial infarction patients.

Methods and Results— Using combined data from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO I) and Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) trials (n=48 422 ST-elevation myocardial infarction patients), we compared the association between initial aspirin dose of 162 versus 325 mg and 24-hour and 7-day mortality, as well as rates of in-hospital moderate/severe bleeding. Results were adjusted for previously identified mortality and bleeding risk factors. Overall, 24.4% of patients (n=11 828) received an initial aspirin dose of 325 mg, and 75.6% (n=36 594) received 162 mg. The 24-hour mortality rates were 2.9% versus 2.8% (P=0.894) for those receiving an initial aspirin dose of 325 versus 162 mg. Mortality rates at 7 and 30 days were 5.2% versus 4.9% (P=0.118) and 7.1% versus 6.5% (P=0.017) among patients receiving the 325 versus 162 mg aspirin. After adjustment, aspirin dose was not associated with 24-hour (odds ratio [OR], 1.01; 95% CI, 0.82 to 1.25), 7-day (OR, 1.00; 95% CI, 0.87 to 1.17), or 30-day (OR, 0.99; 95% CI, 0.87 to 1.12) mortality rates. No significant difference was noted for myocardial infarction or the composite of death or myocardial infarction between groups. In-hospital moderate/severe bleeding occurred in 9.3% of those treated with 325 mg versus 12.2% among those receiving 162 mg (P<0.001). After adjustment, 325 mg was associated with a significant increase in moderate/severe bleeding (OR, 1.14; 95% CI, 1.05 to 1.24; P=0.003).

ConclusionThese data suggest that an initial dose of 162 mg aspirin may be as effective as and perhaps safer than 325 mg for the acute treatment of ST-elevation myocardial infarction.

Monday, January 21, 2008

Digitalis: a dangerous drug in atrial fibrillation? An analysis of the SPORTIF III and V data

Commentaries:
Patient not randomized to Digitalis

Digitalis: a dangerous drug in atrial fibrillation? An analysis of the SPORTIF III and V data

Heart 2008;94:191-196

K Gjesdal, J Feyzi, S B Olsson

ABSTRACT

Objective: In heart failure, digitalis increases exercise capacity and reduces morbidity, but has no effect on survival. This raises the suspicion that the inotropic benefits of digitalis may be counteracted by serious adverse effects. Patients with atrial fibrillation (AF) were studied to clarify this.

Design: In the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF) III and V studies, 7329 patients with AF at moderate-to-high risk were randomised to preventive treatment of thromboembolism, either with warfarin or the oral direct thrombin inhibitor ximelagatran. The survival of users and non-users of digitalis was investigated.

Results: At baseline, 53.4% of the study population used digitalis, and these patients had a higher mortality than non-users (255/3911 (6.5%) vs 141/3418 (4.1%), p<0.001; hazard ratio (HR) = 1.58 (95% CI 1.29 to 1.94)). Digitalis users also had more baseline risk factors. After multivariate risk factor adjustment, the increased mortality persisted (p<0.001; HR = 1.53 (95% CI 1.22 to 1.92 vs 1.23 to 1.92)).

Conclusions: The results suggest that digitalis, like other inotropic drugs, may increase mortality. This may be concealed in heart failure, but be revealed in patients with AF, who need the rate-reducing effect of digitalis, but do not benefit much from an increased inotropy. Cautious interpretation of the data is mandatory since the patients were not randomised with respect to digitalis use.

Amiodarone use after acute myocardial infarction complicated by heart failure and/or left ventricular dysfunction - Mortality

Commentaries:
Obsertvationl study; need to be validate with prospective studies.


Amiodarone use after acute myocardial infarction complicated by heart failure and/or left ventricular dysfunction may be associated with excess mortality

American Heart Journal
Volume 155, Issue 1, Pages 87-93 (January 2008)


Kevin L. Thomas, MDa, Sana M. Al-Khatib, MHS, MDa, Yuliya Lokhnygina, PhDa, Scott D. Solomon, MDb, Lars Kober, MDc, John J.V. McMurray, MDd, Robert M. Califf, MDa, Eric J. Velazquez, MDa


Background
We sought to assess the association of amiodarone use with mortality during consecutive periods in patients with post–acute myocardial infarction with left ventricular systolic dysfunction and/or HF treated with a contemporary medical regimen.

Methods
This study used data from VALIANT, a randomized comparison of valsartan, captopril, or both in patients with acute myocardial infarction with HF and/or left ventricular systolic dysfunction. We compared baseline characteristics of 825 patients treated with amiodarone at randomization with 13 875 patients not treated with amiodarone. Using Cox models, we examined the association of amiodarone use with subsequent mortality during consecutive periods after randomization (days 1-16, 17-45, 46-198, and 199-1096).

Results
Patients treated with amiodarone were older, had higher Killip class, and were more likely to have a history of diabetes mellitus and hypertension. Adjusting for baseline predictors of mortality, we found that amiodarone use was associated with a significant increase in mortality during 3 of the 4 periods: hazard ratio 1.5, 95% CI (1.1-2.0), P = .02, for days 1 to 16; 2.1 (1.5-2.9), P < .001, for days 17 to 45; 1.1 (0.83-1.46), P = .51, for days 46 to 198; and 1.4 (1.2-1.6), P < .001, for days 199 to 1096. Conclusion
In this study, amiodarone use was associated with excess early and late all-cause and cardiovascular mortality. These observational findings are in contrast to earlier randomized trials of amiodarone and need to be validated prospectively.

Atral Fibrillation, Inflamation and CPR levels

Commentaries:

There a need for data , well-designed and blinded longitudinal studies.


The role of the post-cardioversion time course of hs-CRP levels in clarifying the relationship between inflammation and persistence of atrial fibrillation

Heart

E M Kallergis, E G Manios, E M Kanoupakis, H E Mavrakis, S G Kolyvaki, G M Lyrarakis, G I Chlouverakis, P E Vardas
Department of Cardiology, University Hospital of Heraklion, Crete, Greece


ABSTRACT

Objectives: Although recent studies suggest that inflammation is involved in the pathogenesis of atrial fibrillation (AF), it remains controversial whether it is a consequence or a cause of the arrhythmia.

Design: Prospective study.

Setting: Tertiary referral centre.

Patients and Interventions: In 52 patients with persistent AF lasting >3 months, high-sensitivity C-reactive protein (hs-CRP) was measured before and after electrical cardioversion.

Measurements and Results: All patients were successfully cardioverted to sinus rhythm (SR), but the recurrence rate was 23% at 1 month. Baseline hs-CRP was higher in patients with AF recurrence than in those who remained in SR (0.5 (SD 0.18) mg/dl vs 0.29 (SD 0.13) mg/dl, respectively, p<0.001). Similarly, arrhythmia recurrence was associated with greater left atrial diameters (45.4 (SD 3.3) mm vs 40.7 (SD 3.1) mm, respectively, p<0.001). However, logistic regression analysis showed that hs-CRP was the only independent predictor for AF recurrence (p<0.001). Additionally, patients who were in SR on final evaluation had significantly lower hs-CRP levels than at baseline (0.10 (SD 0.06) mg/dl vs 0.29 (SD 0.13) mg/dl, respectively, p<0.001), while those who experienced AF recurrence had similar values on final and on initial evaluation (0.56 (SD 0.24) mg/dl vs 0.50 (SD 0.18) mg/dl, respectively, p = 0.42).

Conclusion: High levels of hs-CRP are associated with an increased risk of AF recurrence after cardioversion. The restoration and maintenance of SR result in a gradual decrease of hs-CRP while AF recurrence has a different effect, suggesting that inflammation is a consequence, rather than a cause, of AF.

Saturday, January 19, 2008

Study Locates Cholesterol Genes; Finds Surprises About Good, Bad Cholesterol

Study Locates Cholesterol Genes; Finds Surprises About Good, Bad Cholesterol

ScienceDaily (Jan. 17, 2008) — An international study of 20,000 people found seven new genes that influence blood cholesterol levels, a major factor in heart disease, and confirmed 11 other genes previously thought to influence cholesterol.

full story

Prescribing Amiodarone - An Evidence-Based Review of Clinical Indications

Prescribing Amiodarone

An Evidence-Based Review of Clinical Indications

Patricia Vassallo, MD; Richard G. Trohman, MD

JAMA. 2007;298:1312-1322.

Context Although amiodarone is approved by the US Food and Drug Administration only for refractory ventricular arrhythmias, it is one of the most frequently prescribed antiarrhythmic medications in the United States.

Objective To evaluate and synthesize evidence regarding optimal use of amiodarone for various arrhythmias.

Evidence Acquisition Systematic search of MEDLINE to identify peer-reviewed clinical trials, randomized controlled trials, meta-analyses, and other studies with clinical pertinence. The search was limited to human-participant, English-language reports published between 1970 and 2007. Amiodarone was searched using the terms adverse effects, atrial fibrillation, atrial flutter, congestive heart failure, electrical storm, hypertrophic cardiomyopathy, implantable cardioverter-defibrillator, surgery, ventricular arrhythmia, ventricular fibrillation, and Wolff-Parkinson-White. Bibliographies of identified articles and guidelines from official societies were reviewed for additional references. Ninety-two identified studies met inclusion criteria and were included in the review.

Evidence Synthesis Amiodarone may have clinical value in patients with left ventricular dysfunction and heart failure as first-line treatment for atrial fibrillation, though other agents are available. Amiodarone is useful in acute management of sustained ventricular tachyarrythmias, regardless of hemodynamic stability. The only role for prophylactic amiodarone is in the perioperative period of cardiac surgery. Amiodarone may be effective as an adjunct to implantable cardioverter-defibrillator therapy to reduce number of shocks. However, amiodarone has a number of serious adverse effects, including corneal microdeposits (>90%), optic neuropathy/neuritis (1%-2%), blue-gray skin discoloration (4%-9%), photosensitivity (25%-75%), hypothyroidism (6%), hyperthyroidism (0.9%-2%), pulmonary toxicity (1%-17%), peripheral neuropathy (0.3% annually), and hepatotoxicity (elevated enzyme levels, 15%-30%; hepatitis and cirrhosis, <3%>

Conclusion Amiodarone should be used with close follow-up in patients who are likely to derive the most benefit, namely those with atrial fibrillation and left ventricular dysfunction, those with acute sustained ventricular arrhythmias, those about to undergo cardiac surgery, and those with implantable cardioverter-defibrillators and symptomatic shocks.

Aspirin 'resistance' linked to increased CV morbidity

Aspirin 'resistance' linked to increased CV morbidity

By Caroline Price

18 January 2008

Br Med J 2008; Advance online publication

MedWire News: Patients who do not respond to aspirin therapy are at increased long-term risk for cardiovascular (CV) morbidity, the results of a systematic review and meta-analysis show.

Such patients, labeled "aspirin resistant," had an approximately four-fold increased risk for nonfatal and fatal cardiovascular, cerebrovascular, or vascular events when taking aspirin compared with those classified as sensitive to aspirin.

"Not only did aspirin resistance have an effect on clinical outcome but this risk was not ameliorated by currently used adjunct antiplatelet therapies," the study authors note.

It is not clear why a significant number of CV disease patients derive no benefit from aspirin therapy, nor how these patients may be identified, explain Michael Buchanan (McMaster University, Hamilton, Ontario, Canada) and colleagues.

Such patients have been termed aspirin resistant because their platelets are not affected in the same way as platelets from individuals who seem to benefit from aspirin therapy. Yet it remains unknown whether these patients simply receive too low an aspirin dose, are not compliant, have differing abilities to absorb aspirin, or have an underlying genetic disposition that makes aspirin ineffective. Furthermore, few studies have addressed the impact of aspirin resistance on clinical outcomes.

To look for any relationship between aspirin resistance and clinical outcomes, Buchanan and team reviewed the literature and conducted a meta-analysis on 20 studies involving 2930 patients with CV disease who were receiving aspirin as an antithrombotic. Patients were classified as aspirin resistant if their platelet response was not inhibited in vitro by aspirin.

Overall, 810 (28%) patients were classified as aspirin resistant. These patients, regardless of underlying clinical symptoms, had a greater risk for death, acute coronary syndrome, failure in vascular intervention, or a new cerebrovascular event.

Indeed, 39% of aspirin-resistant compared with 16% of aspirin-sensitive patients had any cardiovascular event, giving an odds ratio of 3.85 (p<0.001).

The odds ratios for acute coronary syndrome, graft failure, and new cerebrovascular event in aspirin resistant compared with aspirin sensitive patients were 4.06, 4.35, and 3.78, respectively.

Moreover, the odds ratio for mortality for aspirin resistant patients was 5.99 (p<0.003).

A planned sensitivity analysis revealed no evidence of a dose-response relationship between aspirin resistance and any cardiovascular outcome among patients who received aspirin alone or who received a second antiplatelet. Furthermore, patients who were aspirin resistant had no benefit from concomitant therapy with clopidogrel or tirofiban, or both.

Italian cardiologists Giuseppe Biondi-Zoccai (University of Turin) and Marzia Lotrionte (Catholic University, Rome) commented in an accompanying editorial that further trials are needed to clarify whether aspirin resistance is just a nonmodifiable risk factor, or whether more aggressive antithrombotic regimens will benefit patients with aspirin resistance.

However, they cautioned that although clinical trials will help "fill in the gaps," there may be another factor generating interest in aspirin resistance.

"Drug companies may be keen to downgrade aspirin from its leading role as an effective drug in CV disease so that they can substitute it with much more expensive but marginally more effective alternatives," they stated.

Journal

Immunotherapy 'benefits large proportion of heart failure patients'

Immunotherapy 'benefits large proportion of heart failure patients'

By Cher Thornhill

18 January 2008

Lancet 2008; 371: 228-236

MedWire News: Immunomodulation therapy (IMT) appears to prolong life and delay readmission for a large proportion of heart failure patients, a large, placebo-controlled trial suggests.

Guillermo Torre-Amione (Methodist Hospital, Houston, Texas, USA) and co-workers found that heart failure patients with no history of myocardial infarction and those within New York Heart Association (NYHA) class II who receive IMT have around 25% and 40% reductions in a composite of time to death and hospitalization for cardiac reasons.

But editorialists Karen Sliwa (University of Witwatersrand, Johannesburg, South Africa) and Aftab Ansari (Emory University School of Medicine, Atlanta, Georgia, USA) caution that the therapy could raise patients' susceptibility to infections and cancer, or trigger autoimmune disease.

Torre-Amione and team studied 2426 patients with NYHA functional class II-IV chronic heart failure, left ventricular systolic dysfunction, and who had been hospitalized for heart failure or intravenous drug therapy within the past year.

Patients in the treatment arm received IMT on days 1, 2, and 14 and then every 28 days for at least 22 weeks.

For IMT, anticoagulated blood taken from the patients was exposed to ozone and ultraviolet light and then re-injected.

During a mean follow-up of 10.2 months, the incidence of primary events was statistically comparable in the treatment and placebo groups (339 vs 429, HR=0.92).

Torre-Amione et al say the null result "was disappointing in view of increasing evidence that inflammation plays a part in the progression of heart failure."

However, IMT was associated with a 26% reduction in the primary events in patients with no history of myocardial infarction (n=919) and a 39% reduction among patients with NYHA class II heart failure (n=689).

The researchers note that, compared with the entire population, these subgroups consisted of younger patients with baseline variables consistent with less severe disease.

Thus, IMT may only be effective when started early, before permanent cellular damage, they suggest.

In their editorial, Sliwa and Ansari said there are several "potential problems" with the approach taken by Torre-Amione's team.

Susceptibility to opportunistic infections may increase and elimination of potentially malignant cells may decrease. While neither was reported, the effects may be slow to emerge, they commented.

They added: "The study was too short to detect new onset of autoimmune diseases.

"Long-term follow-up of patients receiving this type of therapy should be mandatory."

Journal

Wednesday, January 16, 2008

Calcium Supplements in Older Women Possibly Linked to More Cardiovascular Events

Blog observations about this study:

Calcium supplementation may adversely affect cardiovascular health in older women.

New Zealand researchers randomized nearly 1500 postmenopausal women to either 1 g of calcium or placebo daily; they then measured cardiovascular events over the ensuing 5 years


Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial

Mark J Bolland, research fellow1, P Alan Barber, senior lecturer1, Robert N Doughty, associate professor1, Barbara Mason, research officer1, Anne Horne, research fellow1, Ruth Ames, research officer1, Gregory D Gamble, research fellow1, Andrew Grey, associate professor1, Ian R Reid, professor1
Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand
Correspondence to: I R Reid i.reid@auckland.ac.nz

Abstract

Objective

To determine the effect of calcium supplementation on myocardial infarction, stroke, and sudden death in healthy postmenopausal women.

Design

Randomised, placebo controlled trial.

Setting

Academic medical centre in an urban setting in New Zealand.

Participants

1471 postmenopausal women (mean age 74): 732 were randomised to calcium supplementation and 739 to placebo.

Main outcome measures

Adverse cardiovascular events over five years: death, sudden death, myocardial infarction, angina, other chest pain, stroke, transient ischaemic attack, and a composite end point of myocardial infarction, stroke, or sudden death.

Results

Myocardial infarction was more commonly reported in the calcium group than in the placebo group (45 events in 31 women v 19 events in 14 women, P=0.01). The composite end point of myocardial infarction, stroke, or sudden death was also more common in the calcium group (101 events in 69 women v 54 events in 42 women, P=0.008). After adjudication myocardial infarction remained more common in the calcium group (24 events in 21 women v 10 events in 10 women, relative risk 2.12, 95% confidence interval 1.01 to 4.47). For the composite end point 61 events were verified in 51 women in the calcium group and 36 events in 35 women in the placebo group (relative risk 1.47, 0.97 to 2.23). When unreported events were added from the national database of hospital admissions in New Zealand the relative risk of myocardial infarction was 1.49 (0.86 to 2.57) and that of the composite end point was 1.21 (0.84 to 1.74). The respective rate ratios were 1.67 (95% confidence intervals 0.98 to 2.87) and 1.43 (1.01 to 2.04); event rates: placebo 16.3/1000 person years, calcium 23.3/1000 person years. For stroke (including unreported events) the relative risk was 1.37 (0.83 to 2.28) and the rate ratio was 1.45 (0.88 to 2.49).

Conclusion

Calcium supplementation in healthy postmenopausal women is associated with upward trends in cardiovascular event rates. This potentially detrimental effect should be balanced against the likely benefits of calcium on bone.

Monday, January 14, 2008

ENHANCE - Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone

Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients With Heterozygous Familial Hypercholesterolemia (ENHANCE)

Trial Summary

Title:

Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients With Heterozygous Familial Hypercholesterolemia (ENHANCE)

Trial Sponsor: Merck/Schering-PloughYear

Presented: 2008

Description

The following information was derived from a Merck/Schering-Plough press release from January 14, 2008; full data are to be presented at the 2008 ACC Scientific Session.

Hypothesis

The goal of this trial was to compare the mean change in the intima-media thickness (IMT) measured at three sites in the carotid arteries between patients with Heterozygous Familial Hypercholesterolemia (HeFH) treated with ezetimibe/simvastatin 10/80 mg versus patients treated with high-dose simvastatin 80 mg alone over a two-year period.

Principal Findings

A total of 720 patients with HeFH were randomized in this multinational, randomized, double-blind, active comparator trial: 357 to the ezetimibe/simvastatin arm and 363 to the high-dose simvastatin arm. Images were obtained from the right and left carotid arteries at three sites at baseline, 6, 12, 18, and 24 months. The baseline low-density lipoprotein (LDL) cholesterol levels between the two arms were comparable (319 vs. 318 mg/dl; p=non-significant [NS]). Approximately 80% of patients enrolled in the trial had been on statins previously. The baseline mean carotid IMT measurements were similar between the two arms.

There was no statistically significant difference between the two arms with respect to the primary endpoint, the mean change in carotid IMT. The change from baseline for the ezetimibe/simvastatin arm was 0.0111 mm, compared with 0.0058 mm for the high-dose simvastatin arm (p=0.29).There was no difference in the incidence of cardiovascular clinical events: cardiovascular deaths (0.6 vs. 0.3%), non-fatal myocardial infarction (0.8% vs. 0.6%), non-fatal stroke (0.3% vs. 0.3%), and need for revascularization (1.7% vs. 1.4%) [p=NS for all].

There was, however, a significant reduction in LDL lowering noted in the ezetimibe/simvastatin arm compared with the simvastatin arm (58% vs. 41%; p<0.01).The overall incidence of treatment-related adverse events was similar between the two groups: consecutive elevations of serum transaminases ≥ 3X ULN (2.8% vs. 2.2%), elevated CPK ≥ 10 X ULN (1.1% vs. 2.2%), and elevated CPK ≥ 10X ULN with muscle symptoms (0.6% vs. 0.3%) [p=NS for all]. There were no cases of rhabdomyolysis reported in either arm.

Interpretation

The results of the multicenter, randomized ENHANCE trial seem to suggest that in patients with very high baseline LDL levels, such as those with heterozygous familial hypercholesterolemia, the combination of ezetimibe/simvastatin 10/80 mg does not result in significant changes in the mean carotid IMT at 2 years when compared with high-dose simvastatin 80 mg alone. There was also no difference in the incidence of cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, or need for revascularization, although this study was not powered to study clinical outcomes. The LDL-lowering effect of ezetimibe/simvastatin was greater than that achieved with high-dose simvastatin alone.

Although this was a negative study, it will be interesting to see if larger ongoing trials will be able to demonstrate any relative superiority of the combination of ezetimibe/simvastatin in improving cardiovascular outcomes in high-risk patients as compared with simvastatin alone.

Study DesignRandomized. Blinded. Parallel.
Patients Enrolled: 720
Mean Follow-Up: 24 months

Sunday, January 13, 2008

Commentary:

Physicians and patients shoul boicott Zetia an Vytorin


Is Vytorin about to be renamed Whytorin?


Link:

http://pharmagossip.blogspot.com/2007/11/is-vytorin-about-to-be-renamed-whytorin.html

Matt Herper writes:
Every day millions of people swallow Zetia and Vytorin in the hopes of reducing their risk of heart attacks and strokes, generating $5 billion a year in sales for Merck and Schering-Plough, which produce them.


Do they work?
Despite millions of prescriptions, no study has ever shown that these $3-a-day pills prevent heart attacks, strokes or deaths any better than just taking older drugs like Pfizer's Lipitor or Merck's off-patent Zocor, even though they're proven cholesterol fighters. That's why a two-year delay in a 720-person study aimed at clarifying the issue has cardiologists expressing skepticism and spinning conspiracy theories. If the news were good, the companies would rush it out, the thinking goes. Delay doesn't bode well. "It starts to raise suspicion," says Allen J. Taylor, head of cardiology at Walter Reed Army Medical Center. "The more time it takes, the more you start to naturally wonder what is wrong."


Related:

http://blogs.wsj.com/health/

Risk Of Cardiovascular Mortality Secondary To Androgen Deprivation Therapy For Localized Prostate Cancer


Commentary:

The use of ADT appears to be associated with an increased risk of death from cardiovascular causes in patients undergoing radical prostatectomy for localized prostate cancer.


Risk Of Cardiovascular Mortality Secondary To Androgen Deprivation Therapy For Localized Prostate Cancer

October 17, 2007 issue of the Journal of the National Cancer Institute

13 Jan 2008

UroToday.com - Androgen deprivation therapy (ADT) is associated with metabolic syndrome, which includes the development of type II diabetes mellitus and coronary artery disease. In the October 17, 2007 issue of the Journal of the National Cancer Institute evaluated whether ADT induced metabolic changes result in an increased risk of cardiovascular (CV) death.

The longitudinal, observational prostate cancer registry CaPSURE was used to study a cohort of 4,892 men. Of these, 1,015 patients were treated with ADT with local therapy and 3,977 men were not treated with ADT. ADT was used in 266 patients who had RP and in 749 men who received nonsurgical treatment. The primary endpoint of the study was death due to CV causes.

This was defined as myocardial infarction, sudden cardiac arrest, coronary artery disease, cardiac ischemia, arrhythmia, pulmonary embolism, or stroke.

Median patient age was 64 years and median followup was 3.8 years. Patients receiving radiotherapy, cryotherapy or brachytherapy as primary treatment in combination with ADT were older than men who had RP. The overall median duration of ADT therapy was 4.1 months. The proportion of patients with baseline hypertension and heart disease were similar among those who did and did not receive ADT. The proportion of patients with baseline diabetes was statistically higher in patients using ADT than in patients not using ADT. Analysis of patients treated with RP, both ADT and older age were associated with significantly increased risks of death from CV causes, but the presence of baseline heart disease or diabetes was not. This risk of CV death was evident in patients younger and older than 65 years. The cumulative incidence of death from CV causes among the younger patients using ADT was 3.6%, as compared to 1.2% in those not using ADT. Among patients treated with radiotherapy, brachytherapy or cryotherapy, only older age was associated with an increased risk of death from CV disease. Patients older than age 65 years who were treated with RP and ADT also had higher 5-year estimates of death from CV causes. In multivariable analysis among patients treated with RP, ADT use was associated with increased risk of death from any cause.

Older age, Gleason score greater than 8 and presence of baseline diabetes were also associated with an increased risk of death from any cause. Among those who did not undergo RP, a shorter time to all-cause mortality was not associated with ADT use, but was associated with advancing age.

To access the latest urology news releases from UroToday, go to: http://www.urotoday.com/

Saturday, January 12, 2008

Meta-Analysis of Effect of Statin Treatment on Risk of Sudden Death


Meta-Analysis of Effect of Statin Treatment on Risk of Sudden Death

Title: Meta-Analysis of Effect of Statin Treatment on Risk of Sudden Death

Topic: Arrhythmias

Date Posted: 1/11/2008

Author(s): Levatesi G, Scarano M, Marfisi R, et al.

Citation: Am J Cardiol. 2007;100:1644-1650.


Study Question: Do statins prevent sudden death (SD)?

Methods: This was a meta-analysis of 10 randomized, controlled trials in which a statin was compared with placebo or no therapy. There were a total of 22,275 patients, with 11,136 randomly assigned to receive a statin. The mean age was 60 years, 81% were male, and 69% had a history of myocardial infarction. The mean duration of follow-up was 4.4 years.

Results: The incidence of SD was significantly lower in the statin group (3.0%) than in the control group (3.8%). The 19% reduction in relative risk of SD in the statin group was independent of the extent to which the plasma cholesterol level decreased.

Conclusions: Stains reduce the relative risk of SD by approximately 20% over 4 years of follow-up.

Perspective: A reduction in SD by statins is consistent with the results of implantable cardioverter defibrillator trials that have demonstrated a reduction in the risk of appropriate shocks in patients treated with a statin. There are several possible mechanisms by which statins might reduce the risk of malignant ventricular arrhythmias, including prevention of ischemia and indirect channel effects mediated by alterations in the lipid content of cell membranes. Fred Morady, M.D., F.A.C.C.

Alcohol and long-term prognosis after a first acute myocardial infarction: the SHEEP study

Alcohol and long-term prognosis after a first acute myocardial infarction: the SHEEP study

Eur Heart J 2008 29: 45-53.

Context: Few studies have investigated the relation between alcohol consumption, former drinking, and prognosis after an acute myocardial infarction (AMI), particularly for non-fatal outcomes.

Objective: To investigate the prognostic importance of drinking habits among patients surviving a first AMI.

Design, settings, and patients: A total of 1346 consecutive patients between 45–70 years with a first non-fatal AMI underwent a standardized clinical examination and were followed for over 8 years.

Main outcome measures: Total and cardiac mortality and hospitalization for non-fatal cardiovascular disease in relation to individual alcoholic beverage consumption at the time of AMI and 5 years before inclusion, assessed by a standardized questionnaire administered during hospitalization.

Results: We recorded 267 deaths, and 145 deaths from cardiac causes, during the follow-up period. After adjustment for several potential confounders, hazard ratios for total and cardiac mortality were 0.77 (0.51–1.15) and 0.61 (0.36–1.02) for those drinking >0–<5 g per day, 0.77 (0.50–1.18) and 0.62 (0.36–1.07) for those drinking 5–20 g per day, and 0.89 (0.56–1.40) and 0.69 (0.38–1.25) for those drinking over 20 g per day. Risk of hospitalization for recurrent non-fatal AMI, stroke, or heart failure generally showed a similar pattern to that of total and cardiac mortality. Recent quitters at the time of AMI had a hazard ratio of 4.55 (2.03–10.20) for total mortality. Measures of insulin sensitivity appeared to be the strongest mediators of this association.

Conclusions: Moderate alcohol drinking might have beneficial effects on several aspects of long-term prognosis after an AMI. Our findings also highlight that former drinkers should be examined separately from long-term abstainers. The potential mechanisms that underlie this association still need to be elucidated.

Statin therapy in diabetics supported

Statin therapy in diabetics supported

By Caroline Price

11 January 2008

Lancet 2008; 371: 117-125

MedWire News: Meta-analysis findings demonstrate that statin therapy should be considered in all individuals with diabetes if they are deemed at "sufficiently high" risk for vascular events, conclude the Cholesterol Treatment Trialists' (CTT) Collaborators in The Lancet.

An earlier CTT meta-analysis of 14 randomized trials of statin therapy showed that lowering low-density lipoprotein (LDL) cholesterol by 1 mmol/l reduces the risk of vascular events (myocardial infarction or coronary death, stroke, or coronary revascularization) by around one-fifth in a broad range of high-risk individuals, largely irrespective of baseline lipid levels and conditions, including diabetes.

For the current study, the CTT investigators conducted pre-specified analyses of the same 14 trials to determine whether individuals with diabetes derive the same benefits from statins as those without.

Uncertainties remain over the effects of statins in diabetic individuals on major coronary events, stroke, and the need for revascularization, and whether their benefits are worthwhile in those without a history of occlusive vascular disease, the team explains.

The researchers report that there were 3247 major vascular events over a mean follow-up of 4.3 years among the 18,686 participants who had diabetes.

These participants had a 9% reduction in all-cause mortality per mmol/l decrease in LDL cholesterol (relative risk [RR]=0.91, p=0.02). This reduction was similar in magnitude to the 13% RR reduction per mmol/l decrease in LDL cholesterol RR=0.87, p<0.0001) in the remaining 71,370 patients without diabetes, the researchers say.

The reduction in all-cause mortality reflected significant reductions in vascular mortality (0.87, p=0.008) and death due to coronary heart disease (0.88, p=0.03) per mmol/l reduction in LDL cholesterol in the diabetic individuals, with no significant effect on vascular mortality (RR=0.97).

There was a significant 21% reduction in major vascular events per mmol/l decrease in LDL cholesterol in both participants with and without diabetes.

Statin therapy was also associated with significant reductions in MI or coronary death, coronary revascularization, and stroke among the diabetic participants.

Finally, the proportional risk reductions for major vascular events among diabetic individuals were similar irrespective of history of vascular disease, gender, age, treated hypertension, body mass index, systolic or diastolic blood pressure, smoking history, and renal function.

The authors comment that the consistency of the reduction in major vascular events suggests that the benefit is likely to hold true in other populations with diabetes.

"Consequently, the absolute benefits in any specific population of patients may be best estimated by application of a reduction of about a fifth per mmol/l LDL cholesterol reduction to the relevant age-specific and sex-specific rates for that population," they write.

Journal

Thursday, January 10, 2008

Diagnosis of left-ventricular non-compaction in patients with left-ventricular systolic dysfunction

Diagnosis of left-ventricular non-compaction in patients with left-ventricular systolic dysfunction: time for a reappraisal of diagnostic criteria?

European Heart Journal - January 1, 2008

Kohli SK, Pantazis AA, Shah JS, Adeyemi B, Jackson G, McKenna WJ, Sharma S, Elliott PM.
The Heart Hospital, University College, 16-18 Westmoreland Street, W1G 8PH London, UK.

Aims

Left-ventricular non-compaction (LVNC) is characterized by excessive and prominent left-ventricular (LV) trabeculations and may be associated with systolic dysfunction in advanced disease. We sought to determine the proportion of patients fulfilling LVNC criteria in an adult population referred to a heart failure clinic using current diagnostic criteria.

Methods and results

One hundred and ninety-nine patients [age 63.5 +/- 15.9 years, 124 (62.3%) males] with LV systolic impairment were studied. All underwent clinical examination, electrocardiography, and 2-D echocardiography. The number of patients fulfilling diagnostic criteria for LVNC was retrospectively determined using three published definitions. Results were compared with 60 prospectively evaluated normal controls (age 35.7 +/- 13.5 years; 31 males, 30 blacks). Forty-seven patients (23.6%) fulfilled one or more echocardiographic definitions for LVNC. Patients fulfilling LVNC criteria were younger (P = 0.002), had larger LV end-diastolic dimension (P < 0.001), and smaller left atrial size (P = 0.01). LVNC was more common in black individuals (35.5 vs. 16.2%, P = 0.003). Five controls (four blacks) fulfilled one or more LVNC criteria.

Conclusions

This study demonstrates an unexpectedly high percentage of patients with heart failure fulfilling current echocardiographic criteria for LVNC. This might be explained by a hitherto underestimated cause of heart failure, but the comparison with controls suggests that current diagnostic criteria are too sensitive, particularly in black individuals.

Vitamin-mineral supplement fails to reduce BP

Vitamin-mineral supplement fails to reduce BP

By Caroline Price

09 January 2008

J Hum Hypertens 2008; 121: 43-49

MedWire News: Study findings have failed to find any effect of consuming milk supplemented with additional potassium, calcium, magnesium, selenium, and vitamins C and E on blood pressure (BP).

The results "confirm the discrepancy between dietary intervention studies showing reasonable BP lowering effects and intervention studies with a combination of minerals or vitamins showing no effect," say the authors.

This highlights the need to explore potential BP lowering effects of vitamins and minerals consumed in "natural matrices" in the diet rather than as supplements, they add.

In a research letter to the Journal of Human Hypertension, P de Leeuw (University Hospital Maastricht, The Netherlands) and colleagues explain that dietary intervention studies have shown impressive reductions in BP, probably due in part to the mineral and vitamin components of such diets. Yet interventions with combinations of either minerals or vitamins have provided mixed results.

In the current study, the researchers tested the BP lowering effect of a combination of minerals and vitamins. They randomly assigned 124 adults with untreated mild hypertension to take a supplemented skimmed milk drink or a placebo drink daily for 8 weeks.

The milk was supplemented with 446 mg calcium, 100 mg magnesium, 40 µg selenium, 180 mg vitamin C, 30 mg vitamin E and tocopherol equivalents, and either 1500 mg (high-K) or 750 mg (low-K) potassium per serving.

At the end of the study, office systolic BP had decreased by 4.6, 4.5, and 5.1 mmHg from baseline in the low-K supplement, high-K supplement, and placebo groups, respectively. The differences in BP reduction among groups were nonsignificant.

Reductions in office diastolic BP, pulse pressure, 24-hour systolic BP, 24-hour diastolic BP, and heart rate over the 8 weeks did not differ among the three groups either.

The results "are in contrast with many studies addressing interventions with the individual components," the authors write. They note that the doses of the individual minerals and vitamins may have been too low, and that combinations of vitamins and minerals may counter the effects of the individual components.

Meanwhile, the contrast with findings of dietary interventions may reflect the reduction of components with negative effects by diet replacement, the increased presence of as-yet unidentified components in dietary interventions, or altered bioavailability of nutrients when provided in a dairy matrix.

"Future studies should focus on assessing the effect of subsets of combinations of minerals and vitamins in natural matrices to get a better understanding of the possible antagonistic action between some of these ingredients," de Leeuw and co-authors conclude.

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