Most effective loop diuretic may be the least prescribed for heart failure patients
Researchers from Yale School of Medicine (CT, USA) have carried out a comparative effectiveness study of loop diuretics (commonly known as water pills) for the treatment of heart failure. In their recent publication in the Journal of the American College of Cardiology, the researchers examined data on three widely known loop diuretics, namely furosemide, bumetanide and torsemide.
Existing pharmacological clinical studies of such diuretics have been limited by issues with methodology and insufficient power. However, current data suggest that newer loop diuretics, such as torsemide, may be superior in their oral bioavailability, duration of action, tolerability and outcomes when compared with furosemide.
Data from the TORIC study in 2002 showed that a greater proportion of heart failure patients receiving torsemide improved their functional class compared with those receiving furosemide. However, despite this and other evidence suggesting its increased efficacy, the use of torsemide in clinical practice remains limited.
Using data from the Perspective database, a fee-supported voluntary database of over 500 hospitals in the USA developed by Premier Inc. (NC, USA), the authors, led by Behnood Bikdeli (Yale School of Medicine) studied heart failure hospitalizations during 2009 and 2010 to identify the proportion of patients (aged >18 years) treated with loop diuretics.
Of the 274,515 patients identified with a principal discharge diagnosis of heart failure in the Perspective database, 92% received a form of loop diuretic therapy during their hospital stay. Of these, 87, 3 and 0.4% received furosemide, bumetanide and torsemide alone, respectively. The remaining 10% were treated with a combination of these agents.
Although most patients with heart failure were treated with a form of loop diuretic, only 0.4% of those receiving a single therapy were given the newer agent torsemide, despite suggestions of its increased efficacy compared with older therapies.
Bikdeli summarized the groups‘ findings: “there appear to be potential benefits from using torsemide compared with furosemide, but it is rarely used in practice. Furosemide is the dominantly used loop diuretic in practice; however, if the potential advantages of torsemide over furosemide are proven in subsequent comparative effectiveness studies, this drug might become the preferred treatment of chronic heart failure.”
The authors concluded their article by calling for the commencement of well-designed randomized controlled trials powered for clinical end points such as quality of life, readmission and mortality, in order to determine any differences in the safety and efficacy of loop diuretic agents.
– Written by Hannah Wilson
Source: Bikdeli B, Strait KM, Dharmarajan K et al. Dominance of furosemide for loop diuretic therapy in heart failure: time to revisit the alternatives? J. Am. Coll. Cardiol. 61(14), 1549–1550 (2013).
Commonly used cholesterol calculation miscalculates heart disease risk
Results of a study published in the Journal of the American College of Cardiology promise to shake up the way routine cholesterol testing is analyzed. The study, led by researchers at the Johns Hopkins University School of Medicine (MD, USA), has found that the standard formula used to calculate LDL cholesterol (LDL-C) levels is often inaccurate. The formula, used for decades, underestimates LDL accuracy in the range considered optimum for high-risk patients.
The Friedewald equation, introduced in 1972, is widely used by physicians to asses a patient‘s risk of heart attack and determine the best course of treatment. The equation calculates LDL-C with the following formula: ([total cholesterol-HDL cholesterol]-triglycerides)/5. A higher answer (given in mg/dl) signals a greater risk of arterial plaque formation and potential heart attack. The equation is an estimation rather than an exact measurement and with the new data, inaccuracies in the system could be intensified.
“In our study, we compared samples assessed using the Friedewald equation with a direct calculation of the LDL-C. We found that in nearly one out of four samples in the ‘desirable‘ range for people with a higher heart disease risk, the Friedewald equation had it wrong,” says Seth Martin, a clinical fellow at the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease (MD, USA) and lead author of the study.
The study looked at adults who had undergone lipid profiling by vertical spin density gradient ultracentrifugation (Atherotech, AL, USA) from 2009 to 2011. Friedewald LDL-C was estimated if triglycerides were ≤400 mg/dl, yielding 1,310,440 total patients and 191,333 patients with Friedewald LDL-C <70 mg/dl, which is the typical LDL goal for patients with heart disease. Greater difference in Friedewald versus direct LDL-C occurred at lower LDL-C and higher triglyceride levels. If Friedewald estimated that LDL-C was <70 mg/dl, median direct LDL-C was 9.0 mg/dl higher when triglycerides were 150–199 mg/dl and 18.4 mg/dl higher when triglycerides were 200–399 mg/dl. Of patients with Friedewald LDL-C <70 mg/dl, 23% had a direct LDL-C ≥70 mg/dl (39% if triglycerides were concurrently 150–199 mg/dl; 59% if triglycerides were concurrently 200–399 mg/dl).
Steven Jones (Johns Hopkins Hospital, MD, USA), senior author of the study, believes that based on their data many people – especially those with high triglyceride levels – may have a false sense of assurance that their LDL-C targets have been achieved. “Many patients may think they achieved their LDL-C target when, in fact, they may need more aggressive treatment to reduce their heart disease risk.”
As an alternative to Friedewald, Martin and colleagues suggest that a more accurate way to evaluate risk for patients is to look at non-HDL, which is attained by subtracting HDL from total cholesterol. The resulting non-HDL value, which includes LDL and VLDL, would typically be about 30 points higher than calculating LDL-C under the Friedewald method and it could vary; however, it would provide a better way to assess whether patients need to adjust their medications, or make more significant lifestyle changes. “Most specialists in our field agree at this point that all of those non-HDL components are important,” he says. “Non-HDL cholesterol is a much better target for quantifying risk of plaques in coronary arteries.”
The Friedewald equation tends to underestimate LDL-C most when accuracy is most crucial. Especially if triglycerides are ≥150 mg/dl, Friedewald estimation commonly classifies LDL-C as <70 mg/dl, despite directly measured levels ≥70 mg/dl, therefore “looking at non-HDL cholesterol would make it simpler, more consistent and would enable us to provide our patients with a better assessment,” says Jones.
– Written by Tanya Stezhka
Source: Martin SS, Blaha MJ, Elshazly MB et al. Friedewald estimated versus directly measured low-density lipoprotein cholesterol and treatment implications. J. Am. Coll. Cardiol. doi:10.1016/j.jacc.2013.01.079 (2013) (Epub ahead of print).
HPS2-THRIVE trial shows significant increase in side effects of niacin and statin treatment
Muscle, skin and gastrointestinal problems caused a quarter of patients with occlusive arterial disease to stop treatment in the HPS2-THRIVE trial, the largest randomized study of vitamin B3 (niacin), after a significant increase in adverse side effects when combined with statin treatment. The trial was conducted by researchers from the Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU) at the University of Oxford (UK). Results were published in the European Heart Journal.
Niacin is the oldest lipid-lowering drug with unique antiatherosclerotic properties to help increase levels of HDL cholesterol and decrease levels of LDL cholesterol (LDL-C) and triglycerides in people at risk of cardiovascular problems, such as heart disease and stroke. However, it has a number of dermatological side effects including skin flushing and itching, dry skin, and skin rashes. Laropiprant can reduce flushing by blocking the prostaglandin D2 receptor involved in the process. Therefore, the HPS2-THRIVE study investigated whether combining extended-release niacin with laropiprant (ERN/LRPT), given in addition to an LDL-C-lowering statin (simvastatin), could reduce the risk of cardiovascular problems in high-risk patients with occlusive arterial disease.
With an average of 3.9 years of follow-up, a total of 25,673 patients from China, the UK and Scandinavia were randomized between April 2007 and July 2010 to receive either 2 g of extended-release niacin plus 40 mg of laropiprant or placebo. In addition, all participants received intensive LDL-C-lowering simvastatin therapy (with or without ezetimibe). The ability to remain on the ERN/LRPT regimen for approximately 1 month was initially assessed in 38,369 patients and approximately one-third were excluded (mainly due to niacin side effects).
By the end of the study, 25% of patients taking ERN/LRPT had stopped their treatment, compared with 17% of patients taking placebo. The most common medical reasons for stopping ERN/LRPT were related to skin, gastrointestinal, diabetic and musculoskeletal side effects.
Jane Armitage, Professor of Clinical Trials and Epidemiology and Honorary Consultant in Public Health Medicine at the CTSU said: “We found that patients allocated to the experimental treatment were four-times more likely to stop for skin-related reasons and twice as likely to stop because of gastrointestinal problems, or diabetes-related problems.”
When added to statin-based LDL-lowering therapy, allocation to ERN/LRPT increased the risk of definite myopathy (75 [0.16%/year] vs 17 [0.04%/year]; risk ratio: 4.4; 95% CI: 2.6–7.5; p < 0.0001). “It appeared that this effect was approximately three-times greater among participants in China than those in Europe, for reasons that are not clear,” continued Armitage. “In the placebo arm (i.e. those on statin-based treatment alone), the statin-related myopathy was more common among participants in China than those in Europe. Therefore, in combination with the greater effect of ERN/LRPT on myopathy in China, the excess number of cases of myopathy caused by ERN/LRPT (though low in both regions) was over ten-times greater among participants in China than those in Europe (0.53% per year compared with 0.03% per year).”
Richard Haynes, Clinical Coordinator at the CTSU, said: “although 25% of patients stopped the treatment early, 75% continued on it for approximately four years. Currently, we are analyzing the final data on cardiovascular outcomes from the trial and once we have these we will know whether or not the benefits of the treatment outweigh the myopathy, skin and gastrointestinal problems.”
The coprincipal investigator of the study, Martin Landray, Reader in Epidemiology and Honorary Consultant Physician at the CTSU, said: “previous research had suggested improving cholesterol levels in high-risk patients might translate into a 10–15% reduction in major vascular events such as heart attacks and strokes. In the HPS2-THRIVE study, 3400 of the 25,673 participants suffered a major vascular event over an average of 4 years of follow-up. This means the study has excellent statistical power to discover the effectiveness or otherwise of the ERN/LRPT treatment.”
– Written by Tanya Stezhka
Source: Haynes R, Jiang L, Hopewell JC et al.; The HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle, and liver outcomes and reasons for stopping study treatment. Eur. Heart J. doi:10.1093/eurheartj/eht055 (2013) (Epub ahead of print).
Rosuvastatin protects against kidney injury from imaging dye in acute coronary syndrome patients
Results presented from a Phase IV study at the American College of Cardiology‘s 62nd Annual Scientific Session (CA, USA) demonstrated that popular cholesterol-lowering drug rosuvastatin significantly reduced the rate of acute kidney injury caused by dye used in imaging in acute coronary syndrome (ACS) patients who underwent a coronary procedure, a high-risk patient group for contrast-agent kidney damage.
The number of ACS patients undergoing angiographic procedures is increasing and includes a population that is getting older and has more risk factors. Rosuvastatin was chosen for its anti-inflammatory properties and previously reported clinical benefits in preventing cardiovascular-damaging events. A total of 504 patients were randomly assigned to the statin or control groups. Statin patients received one 40-mg dose of rosuvastatin on admission to the coronary care unit plus a single 20-mg dose daily until discharge and then continued with postdischarge rosuvastatin at 20 mg/day or 10 mg/day, depending on kidney function determined by creatinine clearance. The control group received atorvastatin at 40 mg/day after discharge only.
On the primary end point – contrastinduced acute kidney injury, defined as a rise of creatinine of at least 0.5 mg/dl or 25% from baseline within 72 h – the statin group had significantly better results than controls (6.7 vs 15.1%, respectively).
“The beneficial impact of statin preadministration was consistent in all subgroups and in particular in kidney dysfunction patients shown by creatinine clearance of <60 ml/min, where kidney injury incidence was 8.6 compared with 20.9% in the control group,” said Anna Toso, the study‘s principle investigator at the Division of Cardiology, Misericordia e Dolce Hospital (Prato, Italy).
“Our study shows that early administration of high-dose statin has a protective effect against kidney damage due to contrast medium in patients with ACS,” Toso continued. “The results help define better the timing of early statin administration, which should be given as soon as possible after admission and always before the angiographic procedure to reduce kidney complications, and achieve clinical benefits, even before hospital discharge.”
– Written by Tanya Stezhka
Source: Toso A. Drug protects against kidney injury from imaging dye in ACS patients. Presented at: American College of Cardiology‘s 62nd Annual Scientific Session, San Francisco, CA, USA, 9–10 March 2013.