Rosuvastatin in Older Patients with Systolic Heart Failure

Further information: The Medical Management of Heart Failure from Cardiovascular Medicine, 3rd Edn*

CORONA was a randomized, double-blind, placebo-controlled study of 5011 patients designed to evaluate the use of a statin in patients 60 years old or older who had New York Association class II, III, or IV (NYHA II, III, IV) systolic heart failure (HF) [1]. Prior to this study, patients with systolic HF had been excluded from statin trials, and CORONA was designed to clarify the role of statins for use in this patient population.

Men and women aged 60 years or more  and who had chronic symptomatic systolic HF of ischemic etiology and ejection fraction (EF) of 40% or lower (NYHA class III-IV) or 35% and lower (NYHA class II) were eligible if they were not using or in need of cholesterol lowering drugs. The primary end point was to determine whether rosuvastatin (10 mg daily) reduced the number of patients who suffered from the combined endpoint of cardiovascular mortality or non-fatal myocardial infarction (MI) or non-fatal stroke. Secondary end points were total mortality, any coronary event, cardiovascular mortality, sudden death, fatal MI, death from worsening HF, total number of hospitalization for cardiovascular causes, for unstable angina, and for worsening HF.

The population studied had a mean age of 73 years (n=5011; 24% women), with 37% in NYHA II and 62% NYHA III, EF 31%, total cholesterol 5.2 mmol/L (200 mg/dl). 60% had a history of MI, 63% hypertension, and 30% diabetes. Patients were well treated for HF with 87% on loop or thiazide diuretics, 39% aldosterone antagonists, 91% ACE inhibitor or AT-1 blocker, 75% beta-blocker, and 33% digitalis, 51% on ASA, and 36% on anticoagulants. Compared to the placebo group, patients receiving rosuvastatin had decreased levels of low-density lipoprotein (LDL) cholesterol (difference in groups, 45%; P>0.001) and of high-sensitivity C-reactive protein (CRP) (difference in groups, 37.1%; P<0.001). During a mean follow-up of 32.8 months, the primary outcome occurred in 692 patients in the rosuvastatin group and 732 in the placebo group (hazard ratio [HR] 0.92; 95% confidence interval [CI], 0.83–1.02; P=0.12), and 728 patients and 759 patients, respectively, died (HR, 0.95; 95% CI, 0.86–1.05; P=0.31).

Although rosuvastatin favorably reduced levels of LDL cholesterol and triglycerides and increased levels of high-density lipoprotein cholesterol, as well as having a favorable effect on high-sensitivity CRP, a daily dose of 10 mg of rosuvastatin did not reduce the primary composite cardiovascular outcome or death from any cause when the drug was added to the existing pharmacological therapy in elderly patients with ischemic, systolic HF. However, rosuvastatin did reduce the number of hospitalizations for cardiovascular causes, in addition to the favorable effects it had on cholesterol levels and CRP. There were no more episodes of liver, kidney, or muscle dysfunction in the rosuvastatin group than in the placebo group.

[1] Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357:1477-86

Note: You may need subscriptions to access content from links on this page. You are responsible for obtaining these subscriptions.

* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.

Cardiac-Resynchronization Therapy in Heart Failure with Narrow QRS Complexes

Further information: The Medical Management of Heart Failure from Cardiovascular Medicine, 3rd Edn*

The RethinQ study [1] was a prospective, multi-center, randomized, double-blind, controlled study, and the objective was to evaluate the effectiveness of cardiac resynchronization therapy (CRT) for patients with a narrow QRS interval (<130 msec). Although a narrow QRS interval is typically defined as an interval of less than 120 msec, patients with a QRS interval of 120 to 130 msec were included to provide additional data on this understudied group.

In 34 centers, 172 patients with a narrow QRS interval were enrolled if they also had an indication for an implantable cardioverter-defibrillator (ICD), ejection fraction (EF) <35%, New York Heart Association (NYHA) class III heart failure (HF), and evidence of mechanical dyssynchrony by 2D echocardiography. The primary efficacy end point was the proportion of patients who had an increase of at least 1.0 ml/kg body weight/min in peak oxygen consumption during cardiopulmonary exercise testing at 6 months after baseline. The secondary efficacy end points included improvement in the quality-of-life score (QOL) and the NYHA class at 6 months after baseline.

At six months, analysis was performed on the data for the 76 patients in the CRT group and the 80 patients in the control group, and neither group differed significantly in the proportion of patients with the primary end point (46% and 41% respectively). There was no significant difference between groups in QOL score, results on the 6-minute walk test, or echocardiographic measures. However, the CRT arm had more patients who improved by one or more NYHA class than the control arm (54% to 29%; P=0.006). The authors of the study concluded that CRT did not improve peak VO2 during exercise testing at 6 months, nor was there improvement in QOL, 6-minute walk, or echocardiography measures in patients with a QRS interval of less than 130 msec. The CRT group did show significant improvement in NYHA class. However, in the subgroup of patients with a QRS interval of 120 msec to 130 msec, there was benefit from CRT, indicating that additional testing is warranted in this patient group.

[1] Beshai JF, Grimm RA, Nagueh SF, et al. Cardiac-resynchronization therapy in heart failure with narrow QRS complexes. N Engl J Med 2007;357: 2461-71

Note: You may need subscriptions to access content from links on this page. You are responsible for obtaining these subscriptions.

* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.

Influence of Nonfatal Hospitalization for Heart Failure on Subsequent Mortality in Patients with Chronic Heart Failure

Further information: The Medical Management of Heart Failure from Cardiovascular Medicine, 3rd Edn*

The Candesartan in a Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) study was conducted in 2003 and consisted of three independent, placebo-controlled studies in patients with New York Heart Association (NYHA) class II-IV congestive heart failure. The results of CHARM trials provided powerful support for the concept that angiotensin receptor blockers have a favorable effect on the course of heart failure (HF). Data from the CHARM trials were used in the present study [1] to evaluate the influence of nonfatal hospitalization for heart failure on subsequent mortality rates in a broad spectrum of heart failure patients.

Of the 7599 patients enrolled in the CHARM trials, 7572 were included in the present analysis, and of that number, 1455 had been hospitalized at least once for HF. Of them, 869 patients survived to the end of the trials, and 586 patients died after discharge. Patients with previous HF hospitalizations had a significantly increased all-cause mortality after discharge compared with patients never hospitalized for HF (hazard ratio [HR]=4.55, P<0.001). Risk of death after discharge increased with each additional HF hospitalization, with almost a 30% increase in risk for patients who had previously been admitted to the hospital with HF on two or three occasions. If the patients stayed in the hospital 22 days, they were more likely to die after discharge that those with hospital stays of up to 7 days (HR=2.4). Risk of death was found to be highest in the first month of discharge and declined over time, especially for death resulting from HF progressions and for sudden cardiac death.

Results of this study showed that hospitalization for HR, including duration and frequency, are important predictors of increased subsequent death after discharge in symptomatic chronic HF patients with reduced or preserved left ventricular ejection fraction. Risk was greatest early after discharge, but declined over time. Findings may lead to identification of HF patients at greatest risk of dying and suggest a role for increased surveillance in early discharge period.

[1] Solomon SD, Dobson J, Pocock S, et al. Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation 2007;116:1482-87

Note: You may need subscriptions to access content from links on this page. You are responsible for obtaining these subscriptions.

* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.

Carvedilol for Children and Adolescents with Heart Failure

Further information: The Medical Management of Heart Failure from Cardiovascular Medicine, 3rd Edn*

The first paper [1] represents a multicenter, randomized, double-blind, placebo-controlled study of 161 children and adolescents with symptomatic, systolic heart failure (HF) conducted in 26 centers to evaluate the effects of a beta blocker, carvedilol, in children and adolescents (18 years or younger; median age of 3).

The patients’ HF etiology included dilated cardiomyopathy and congenital heart disease, and all patients had received standard HF therapy for at least 1 month prior to randomization, including ACE inhibitors, unless contraindicated or not tolerated. Patients were randomized to twice-daily dosing with placebo (n=54), low-dose carvedilol (0.2 mg/kg per dose if weight <62.5 kg or 12.5 mg per dose if weight ≥62.5 kg) or high-dose carvedilol (0.4 mg/kg per dose if weight ≥62.5 kg) in a double-blind manner following ratio of 1:1:1, and patients were stratified according to whether each patient’s systemic ventricle were left or right. The primary endpoint was a composite measure of HF outcomes in patients receiving carvedilol (low- and high-dose combined) versus placebo. Secondary outcomes included individual components of this composite, echocardiographic measures, and plasma β-type natriuretic peptide levels.

There was no significant difference between the combined carvedilol and placebo with regard to the percentage of patients who improved (56% vs 56%, respectively), worsened (24% vs 30%, respectively), or were unchanged (19% vs 15%, respectively) during the course of the study. The rates of worsening were lower than expected. The odds ratio (OR) for worsened outcome for patients in the combined carvedilol group versus the placebo group was 0.79 (95% confidence interval [CI], 0.36–1.59; P=0.47). A prespecified subgroup analysis noted significant interaction between treatment and ventricular morphology (P=0.02), indicating a possible differential effect of treatment between patients with a systemic left ventricle (beneficial) and those whose systemic ventricle was not a left ventricle (nonbeneficial). Carvedilol treatment was not associated with improvement in HF class or in global assessment scores (56% improved in all three arms of the study), and the condition worsened in 24% of the carvedilol groups and in 30% of the placebo group. Possibly the etiology of HF, i.e. dilated cardiomyopathy or congenital heart disease in children versus ischemic heart disease in adults, may account for the variable outcomes.

Although experience with randomized trials in pediatric cardiology is limited, the US Food and Drug Administration’s requirements for licensing of devices and the mandate to collect data to determine the safety and efficacy of new pharmaceutical agents in children has meant that randomized trials in children have been financed by industry. The editorial [2] reports on the results from a randomized trial of carvedilol use for children with HF, and disappointingly, participants did not benefit from treatment.

[1] Shaddy RE, Boucek MM, Hsu DT, et al. Carvedilol for children and adolescents with heart failure. JAMA 2007;298:1171-79

[2] Gidding SS. The importance of randomized controlled trials in pediatric cardiology. JAMA 2007;298:1214-16

Note: You may need subscriptions to access content from links on this page. You are responsible for obtaining these subscriptions.

* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.

Prophylaxis of Venous Thromboembolism with Idraparinux

Further information: Venous Disease from Cardiovascular Medicine, 3rd Edn*

Although the standard therapy for the treatment of both venous thromboembolism (VTE) and pulmonary embolism (PE) is unfractionated heparin or low-molecular-weight heparin (LMWH), followed by a vitamin K antagonist (VKA), two trials were conducted by the van Gogh investigators using Idraparinux, a long-acting inhibitor of activated factor X, as a substitute for standard treatment [1]. Of the two separate, randomized, open-label noninferiority trials, the first enrolled 2904 patients and compared the efficacy and safety of Idraparinux with standard therapy in deep venous thrombosis (DVT), and in the second study of 2215 patients, a similar comparison was made in patients with PE. The hypothesis tested was that Idraparinux alone in a fixed dose can replace the combination of unfractionated heparin or LMWH with a VKA.

Patients received either subcutaneous Idraparinux (2.5 mg once weekly) or heparin followed by an adjusted-dose VKA for either 3 or 6 months. The primary efficacy outcome was the 3-month incidence of symptomatic recurrent DVT (nonfatal or fatal).

In the study of patients with VTE, the incidence of recurrence at day 92 was 2.9% in the Idraparinux group as compared with 3.0% in the standard-therapy group [odds ratio, 0.98; 95% confidence interval (CI), 0.63–1.50], and the result satisfied the noninferiority requirement. At 6 months, the hazard ratio for Idraparinux was 1.01. The rates of clinically relevant bleeding at day 92 were 4.5% in the Idraparinux group and 7.0% in the standard-therapy group (P=0.004). At 6 months, the bleeding rates were similar. However, in the study of patients with PE, the incidence of recurrence at day 92 was 3.4% in the Idraparinux group and 1.6% in the standard-therapy group (odds ratio, 2.14%; 95% CI, 1.21–3.78), a finding that did not meet the noninferiority requirement. The death rate was significantly higher in the Idraparinux group (5.1% vs 2.9%, P=0.006), which was mainly due to fatal PE.

The second study [2] was a multicenter, randomized trial to evaluate the safety and efficacy of a 6-month extension of prophylaxis against recurrent VTE using Idraparinux (long-acting inhibitor of activated X) in patients initially receiving 6 months of prophylaxis with an anticoagulant. Patients with confirmed systemic deep VTE or PE were eligible if they had been treated either in previous van Gogh studies or in outside studies for 6 months with an anticoagulant or in VTE studies that used Idraparinux. The extended prophylaxis trial assigned 1215 patients who had 6 months of standard therapy or Idraparinux to 6 months of weekly 2.5 mg injections of Idraparinux or placebo. The primary efficacy outcome was the incidence of symptomatic recurrence of VTE, defined as objectively documented recurrent PE, VTE, or death attributed to PE.

During the 6 months of randomly assigned treatment, six of 594 patients in the Idraparinux group (1.0%) and 23 of 621 patients in the placebo group (3.7%) had symptomatic, objectively confirmed VTE. The reduction in the relative risk with Idraparinux was 72.7% (95% CI, 33.5–88.8; P=0.0002). In patients initially having PE, a recurrent event occurred in three of 283 (1.1%) in the Idraparinux group and in 13 of 304 in the placebo group 4.3%, P=0.002. Among patients who had VTE only, three of 311 patients (1.0%) in the Idraparinux group had a recurrent event, as compared with 10 of 317 patients (3.2%) in the placebo group (P=0.09) Major bleeding occurred in 11 of 594 patients in the Idraparinux group (1.9%) and in none of the 621 patients in the placebo group (P<0.001). A higher incidence of major bleeding was observed in patients who had received Idraparinux before randomization than in those who had received a VKA (3.1% vs 0.9%, P=0.06). In patients with VT who had completed 6 months of anticoagulant therapy, an additional 6 months of Idraparinux reduced the frequency of recurrent VT to 1.0%, as compared with 3.7% in the placebo group. However, there was an excess of major bleeding episodes, including fatal bleeding, in the Idraparinux group (in 1.9% of patients versus none in the placebo group).

These observations suggest a prolonged risk of hemorrhage in patients treated with Idraparinux for more than 6 months; therefore, the benefit of such treatment is marginal.

[1] The van Gogh Investigators. Idraparinux versus standard therapy for venous thromboembolic disease. N Engl J Med 2007.;357:1094-04

[2] The van Gogh Investigators. Extended prophylaxis of venous thromboembolism with Idraparinux. N Engl J Med 2007.;357:1105-12

Note: You may need subscriptions to access content from links on this page. You are responsible for obtaining these subscriptions.

* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.

Dronedarone for Maintenance of Sinus Rhythm in Atrial Fibrillation or Flutter

Further information: Atrial Fibrillation and Flutter from Cardiovascular Medicine, 3rd Edn*

The authors of this study conducted two parallel, identical, double-blind, randomized trials to test a new drug designed to maintain sinus rhythm in atrial fibrillation or atrial flutter [1]. The drug, dronedarone, is chemically related to amiodarone, but has less risk of important adverse effects. The EURIDIS Trial was conducted in 14 European countries and the ADONIS Trial was conducted in the US, Canada, Australia, and South America.

To qualify for the trial, patients were of either sex and were at least 21 years old, having had at least one episode of atrial fibrillation (AF) in the preceding 3 months, and were in sinus rhythm for at least 1 h before randomization. In the two trials, 828 patients received 400 mg of the drug twice daily and 409 received placebo. Patients transmitted electrocardiograms on days 2, 3, and 5; at months 3, 5, 7, and 10; whenever they had symptoms; and at nine scheduled visits during a 12-month period. The primary endpoint was the time to the first recurrence of atrial fibrillation or atrial flutter.

In the non-European trial, the median times to the recurrence of arrhythmia were 59 days in the placebo group and 158 days in the dronedarone group (P=0.002). When arrhythmia recurred in the non-European group, the mean (±SD) ventricular rate was 116.6±31.9 beats per minute and the placebo group was 104.6±27.1 beats per minute (P<0.001). In the European trial, the median times to first arrhythmia were 41 days in the placebo group and 96 days in the dronedarone group (P=0.01), and when arrhythmia recurred in the European trial, the mean ventricular rate was 117.5±29.1 beats per minute in the placebo group and 102.3±24.7 beats per minute in the dronedarone group (P<0.001).

The trials showed that the rates of the first recurrence of AF and of the first recurrence at one year were significantly reduced with dronedarone as compared with placebo. Dronedarone also reduced the ventricular rate in atrial fibrillation during recurrences of arrhythmias. 
 
[1] Singh BN, Connolly SJ, Crijns HJGM, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 2007;357:987-93

Note: You may need subscriptions to access content from links on this page. You are responsible for obtaining these subscriptions.

* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.

ICDs for primary prevention of sudden death

Further information: Sudden Cardiac Death from Cardiovascular Medicine, 3rd Edn*

Sudden cardiac death is a leading cause of mortality in the United States. Evidence from several major clinical trials supported the use of implantable cardioverter-defibrillators (ICD) for primary prevention of sudden death in patients who met certain criteria, and subsequently, Medicare coverage expanded to include their use. However, data show that many apparently eligible beneficiaries do not receive them.

Two significant articles [1,2] on the disparities regarding women and minorities in the use of ICDs were published in the October 3, 2007 issue of The Journal of the American Medical Association. In an accompanying Editorial by Rita Redberg [3], data regarding the disparities covered in both articles were summarized, showing that women, black men, and black women were implanted significantly fewer times than while men. Dr. Redberg also addressed the possible reasons that ICD implantation differed, such as clinical factors, age, co-morbidities, and patient refusal. However, after also examining benefit outcomes data, particularly in patients not receiving ICD implantation, Dr. Redberg raised a fundamental question, “Are too few ICDs for primary prevention being planted in women and minorities or are too many ICDs being implanted in white men?” She concluded that while the two articles on the subject in this issue of JAMA were important, they actually highlighted the importance of studies that would include clinical outcomes, such as survival and quality of life after ICD implantation to determine if all patients receiving the ICDs were benefiting.

Data from a 5% national sample of research-identifiable files obtained from the US Centers for Medicare and Medicaid Services for the period 1991–2005 were analyzed to examine the sex differences in ICD use for primary and secondary prevention of sudden cardiac death (SCD) [1]. Patients were 65 years of age or older and had Medicare-for-service coverage and in the primary prevention cohort (n=65,917 men and n=70,504 women), patients had been diagnosed with a heart attack, heart failure, or a cardiomyopathy, but no prior cardiac arrest or ventricular tachycardia (VT). In the secondary prevention cohort [n=52,252 men and n=47,411 women], patients had been diagnosed with cardiac arrest or VT.

In the 2005 primary prevention group, 32.3 per 1000 men and 8.6 per 1000 women received an ICD within 1 year of entering the study. Men were more likely than women to receive an ICD (hazard ratio [HR] 3.15; 95% confidence interval [CI], 2.86–3.47). Of men and women alive 180 days after study entry, the hazard of mortality in the subsequent year was not significantly lower among those who received an ICD (HR, 1.01; 95% CI, 0.82–1.23). In the secondary prevention group, 102.2 per 1000 men and 38.4 per 1000 women received an ICD. Controlling for demographic and comorbid factors, men were more likely than women to receive an ICD (HR 2.44; 95% CI, 2.30–2.59). Of the men and women alive at 30 days after study entry, the hazard of mortality in the subsequent year was lower among those who received an ICD (HR, 0.65; 95% CI, 0.60–0.71). Thus, in the Medicare population, women were significantly less likely than men to receive an ICD for primary and secondary prevention of SCD. However, sex differences in the use of ICDs reflect a variety of factors, including age, expectation for survival, comorbidity factors, and clinical characteristics, but there was no available information regarding patient refusal.

The study discussed in the second paper [2] is an observational analysis of 13,034 patients admitted between January 2005 and June 2007 with HF and left ventricular ejection fraction (LVEF) of 30% or less. Patients were discharged alive from hospitals in the American Heart Association’s Get with the Guidelines Heart Failure quality improvement program. In patients eligible for an ICD, 4615 (35.4% had received an ICD at discharge (1614 with new ICDs, 527 with planned ICDs, and 2474 with prior ICDs). ICDs were used in 375 of 1329 eligible black women (28.2%), 754 of 2531 white women (29.8%), 660 of 1977 black men (33.4%), and 2356 of 5403 white men (43.6%) (P<0.001). After adjustment for patient characteristics and hospital factors, the adjusted odds of CDS use were 0.73 (95% CI, 0.60–0.88) for black men, 0.62 (95% CI, 0.56–0.68) for white women, and 0.56 (95% CI, 0.44–0.71) for black women, compared with white men. The differences were not attributable to the proportions of women and black patients at participating hospitals or to differences in the reporting of LVEF. Of patients hospitalized with HF or LVEF, 30% are discharged frequently without an ICD, and there are significant disparities between the use of ICDs in women and black men.

[1] Curtis LH, Al-Khatib SM, Shea AM, et al. Sex differences in the use of implantable cardioverter-defibrillators for primary and secondary prevention of sudden cardiac death. JAMA 2007;298:1517-24

[2] Hernandez AF, Fonarow GC, Liang L, et al. Sex and racial differences in the use of implantable cardioverter-defibrillators among patients hospitalized with heart failure. JAMA 2007;298:1525-32

[3] Redberg RF. Disparities in Use of Implantable Cardioverter-Defibrillators: Moving Beyond Process Measures to Outcomes Data (Editorial). JAMA 2007;298:1564-66

Note: You will need subscriptions to access content from links on this page. You are responsible for obtaining these subscriptions.

* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.

Common Long-QT Syndrome Mutation KCNQ1/A34IV in Patients with Different Ethnic Backgrounds

Further information: Sudden Cardiac Death from Cardiovascular Medicine, 3rd Edn*

In an effort to determine whether the high arrhythmic risk associated with the LQTS type 1 (LQT1)-causing mutation (KCNQ1-A341V) was caused directly by A341V or if it were ethnic-specific in a South African founder population, the current study on 78 KCNQ1-A341V genotype-specific patients (mean of 3.7±2.8 affected subjects per family) was conducted through an international collaboration involving 10 centers from eight countries [1]. Although the researchers had assumed that the unexpected clinical phenotype was caused directly by this particular missense mutation, they could not exclude the possibility that clinical severity was not mediated by KCNQ1-A341V, but instead by other genetic factors present in the families who had all lived in South Africa (SA) for more than 300 years.

The authors compared the 78 patients with 166 SA patients with A341V and with 205 non-A341VLQT1 patients. In the two A341V populations composed of SA and non-SA patients, the probability first event through 40 years of age was similar (76% and 82%), and the QTc was 484±42 versus 485±45 ms (P=NS). Compared with the 205 non-A341V patients with the same median follow-up (30 vs 32 years), the 244 A34V1 patients were more likely to have cardiac events (75% vs 24%), were younger at first event (6 vs 11 years), and had a longer QTc (485±43 vs 465±38 ms) (all P<0.001). Arrhythmic risk remained higher (P=0.0001) even when the A341V patients were compared with non-A341V patients with mutations either localized to transmembrane domains or exhibiting a dominant-negative effect. A341V patients had more events despite β-blocker therapy.

The authors concluded that the A341V location on the KCNQ1 gene is associated with an unusual clinical severity independent of family origin; patients with this mutation are at greater risk for cardiac events compared to the general LQT1 population; and this clinical phenotype is not fully explained by the biophysical properties of the mutation. Recurrences of cardiac events were found despite β-blocker therapy and were more frequent in KCNQ1-A341V patients than in LQT1 patients without this specific mutation. The authors recommended careful follow-up and management of the A341V patients.

[1] Croitti L, Spazzolini C, Schwartz PJ, et al. The common long-QT syndrome mutation KCNQ1/A34IV causes unusually severe clinical manifestations in patients with different ethnic backgrounds. Circulation 2007;116:2366-75

Note: You may need subscriptions to access content from links on this page. You are responsible for obtaining these subscriptions.

* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.

Thiazolidinediones in the treatment of type 2 diabetes

Further information: Endocrine Disorders and the Heart from Cardiovascular Medicine, 3rd Edn*

Thiazolidinediones are a group of drugs efficacious in achieving glycemic control and widely used in the treatment of type 2 diabetes. Their success in achieving glycemic control created interest in determining if they also might reduce the cardiovascular complications of diabetes mellitus. However, recent reports of an increase in heart failure in the use of one drug in the class, pioglitazone, resulted in an evaluation of 19 trials in which the drug was used [1].

The meta-analysis included only randomized, double-blind, placebo-controlled trials, and in the study, 16,390 patients were analyzed. The primary outcome was a composite of death from any cause, nonfatal myocardial infarction (MI), or nonfatal stroke, and secondary outcome was the incidence of serious heart failure.

Death, MI, or stroke occurred in 375 of 8554 patients (4.4%) in patients receiving Pioglitazone and in 450 of 7836 patients (5.7%) receiving control therapy [Hazard Ratio (HR), 0.82; 95% Confidence Interval (CI), 0.72–0.94; P=0.005]. Serious heart failure was reported in 200 (2.3%) patients receiving pioglitazone and in 139 patients (1.8%) on control therapy (HR, 1.41; 95% CI, 1.14–1.76; P=0.002), but without an increase in mortality.

The findings of this meta-analysis provide evidence that Pioglitazone is associated with a significantly lower risk of death, MI, or stroke, and that although there is evidence of increased fluid retention and heart failure, the risks do not appear to negate the beneficial effects of the drug and an apparent favorable influence on risk of death, MI, and stroke.

Another drug in the thiazolidinedione class, rosiglitazone, has also been used for glycemic control in the treatment of type 2 diabetes mellitus. However, it has recently been associated with a spectrum of serious adverse events, and the authors of the second study [2] addressed the question of whether or not the drug should remain as an option for treatment. After searching the MEDLINE clinical trials database for randomized, controlled trials of patients with long-term treatment of Rosiglitazone, four studies that included 14,291 patients were selected and reviewed for evidence of MI, heart failure, and cardiovascular mortality.

Rosiglitazone was found to increase the risk of MI compared with control (n=94/6421 vs 83/7870; Relative Risk (RR) 1.42; 95% CI, 1.06–1.91; P=0.02). Also, the RR of heart failure compared with placebo increased (102/6421 vs 62/7870; RR, 2.09; 95% CI, 1.52–2.88; P<0.001). Data also showed that rosiglitazone had no significant increase in risk of cardiovascular mortality (n=59/6421 vs 72/7870; RR, 0.90; 95% CI, 0.63–1.26; P=0.53). There was no evidence of statistical heterogeneity among the trials, and Rosiglitazone had no effect on all-cause mortality (n=146/6421 vs 180/7870; RR, 0.99; 95% CI, 0.80–1.23; P=0.92).

The data suggest that there is more harm than benefit to patients in the use of Rosiglitazone, and that safer alternatives are available. However, adequate cardiovascular risk factor control that includes the use of cardioprotective drugs will help to reduce the likelihood of harm, and on November 14, 2007, the FDA asked the makers of rosiglitazone to add a boxed warning (their strongest form of warning) to their package insert stating that the drug is associated with an increased risk of angina or MI. The warning is a reasonable approach until further prospective data are available to define the absolute risks.

[1] Lincoff MA, Wolski K, Nicholls SJ, Nissen S. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus. a meta-analysis of randomized trials. JAMA 2007;298:1180-88

[2] Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 2007;298(10):1189-95

Note: You may need subscriptions to access content from links on this page. You are responsible for obtaining these subscriptions.

* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.

Long-Term Follow-Up of the West Scotland Coronary Prevention Study

Further information: Management of Cholesterol Disorders from Cardiovascular Medicine, 3rd Edn*

This study [1] is the report of a 10 year follow-up of the West of Scotland Coronary Prevention Study (WOSCOPS), a 5-year, randomized, double-blind, placebo-controlled clinical trial to evaluate the use of pravastatin in 6595 middle-aged men without a history of myocardial infarction (MI).

The results of the WOSCOPS trial showed that after 5 years, there was a reduction in the combined outcome of death from definite coronary heart disease or definite nonfatal myocardial infarction (MI) from 7.9 % in the placebo group to 5.5% in the treatment group (P=0.001), and the risk of death from definite or suspected coronary heart disease was reduced from 1.9% to 1.3% (P=0.04). Even though data from the results of the original trial showed significant benefit, an extended follow-up was conducted, and the goals of the long-term follow-up were to monitor the use of cholesterol-lowering therapy for five years after the end of the study, and to assess ongoing safety and efficacy by collecting data on clinical events for approximately 10 years after the end of the study.

In the original study, final visits occurred in 1995, pravastatin or placebo was withdrawn, and patients were returned to the care of their primary physicians. At that time, lipid lowering therapy was not used for prevention; therefore, the physicians’ decision regarding the use of statin therapy was not based on specific guidelines. Designed by the authors of the original study, the post-trial study compared outcomes of interest for the two original study groups, pravastatin and placebo, regardless of subsequent use of lipid-lowering therapy in the post-trial period. Events during the original trial period and the 5 years of follow-up, in the post-trial period of approximately 10 years, and during the full period of follow-up of approximately 15 years were calculated for the composite cardiovascular endpoints.

This follow-up study found evidence of an ongoing reduction in the risk of major coronary events among participants in the treatment group. The report concluded that in men with hypercholesterolemia, but without a history of MI, statin treatment for an average of 5 years provided an ongoing reduction in the risk of coronary events for an additional period of up to 10 years. There was a no evidence of an overall increase in the risk of death from noncardiovascular causes, cancer, or in the evidence of cancer.

[1] Ford I, Murray H, Packard CJ, et al. Long-term follow-up of the West Scotland Coronary Prevention Study. N Engl J Med 2007; 357:1477-86

Note: You will need subscriptions to access content from links on this page. You are responsible for obtaining these subscriptions.

* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.