2 Minute Medicine Rewind April 7 – April 14, 2014

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In this section, we will highlight the key high-impact studies, updates, and analyses published in medicine during the past week.

Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection

Ledipasvir and Sofosbuvir for Previously Treated HCV Genotype 1 Infection

The current FDA-approved regimen for treatment of Hepatitis C (HCV) genotype 1 infection (sofosbuvir (nucleotide polymerase inhibitor) or simeprevir (protease inhibitor), peginterferon, and ribavirin) has many side effects, primarily due to peginterferon and ribavirin. Ledipasvir is a new HCV NS5A inhibitor which appears to have potent anti-HCV activity. In these pharmaceutical-sponsored, open-label, multicenter, randomized phase 3 trials, 870 previously untreated and 441 previously treated (without sustained virologic response) patients with HCV genotype 1 infection were randomized in a 1:1:1:1 ratio to receive ledipasvir-sofosbuvir for 12 weeks, ledipasvir-sofosbuvir + ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir + ribavirin for 24 weeks. The primary outcome for both trials was sustained virologic response (SVR) at 12 weeks post-treatment. Among treatment-naïve patients, SVR was similarly high among all treatment groups, ranging from 97-99% – superior to the historical response rate of 60% (p<.001). Among previously treated patients with virological relapse, SVR was achieved in 94% (ledipasvir-sofosbuvir for 12 weeks), 96% (ledipasvir-sofosbuvir + ribavirin for 12 weeks), 99% (ledipasvir-sofosbuvir for 24 weeks), and 99% (ledipasvir-sofosbuvir + ribavirin for 24 weeks) of participants, compared to a historical response rate of 25% (p<.001 for superiority). Previously treated patients with cirrhosis benefited significantly from longer treatment duration – 82-86% SVR for 12 weeks, compared to 99% for those who were treated for 24 weeks, p=0.007). Fewer side effects and adverse events were reported among groups not receiving ribavirin. 

A Controlled Trial of Renal Denervation for Resistant Hypertension

Resistant hypertension, which is uncontrolled despite maximal medical therapy, affects up to 10% of patients diagnosed with hypertension. Renal artery denervation has been demonstrated in a number of smaller, nonrandomized and/or unblinded studies to significantly reduce blood pressure in patients with resistant hypertension. In this randomized controlled, pharmaceutical-sponsored trial, 535 patients were randomized in a 2:1 ratio to receive catheter-based radiofrequency renal artery denervation or a sham procedure (renal angiography only) to study the effect on participants’ office systolic blood pressure at 6 months compared to their baseline, with a superiority margin of 5mmHg. Participants in both groups experienced significant changes in systolic blood pressure between baseline and 6 months (p<0.001), but the between-group difference was not significant (-14.13+23.92mmHg vs -11.74+25.94mmHg in the denervation vs sham groups, respectively, difference of -2.39mmHg, 95%CI -6.89-2.12; p=0.26). Secondary outcomes of change in ambulatory blood pressure and change in home blood pressure (systolic and diastolic) were also similar between the denervation and sham groups (-6.75+15.11mmHg vs -4.79+17.25mmHg, respectively, difference of -1.96mmHg, 95%CI -4.97 to 1.06, p=0.98). 

Comparison of Application of the ACC/AHA Guidelines, Adult Treatment Panel III Guidelines, and European Society of Cardiology Guidelines for Cardiovascular Disease Prevention in a European Cohort

The new cardiovascular disease guidelines published by the American College of Cardiology/American Heart Association (ACC/AHA) eliminated LDL targets and instead based treatment with statins on a new 10-year hard atherosclerotic cardiovascular disease (ASCVD) prediction model, with a treatment threshold of 7.5%. These new guidelines have not been compared with existing guidelines. In this retrospective analysis, researchers used data from prospective cohort of 4854 Europeans ages 55+ to calculate 10-year risks using the new ACC/AHA guidelines (all coronary heart disease and stroke), Adult Treatment Panel III (ATP-III) guidelines (coronary heart disease), and European Society of Cardiology (ESC) guidelines (cardiovascular disease mortality). ACC/AHA guidelines recommended treatment for 96% of men and 66% of women, compared to 52% and 35%, respectively, if following the ATP-III guidelines, and 66% and 39%, of men and women, respectively, based on the ESC guidelines. The ACC/AHA and ATP-III guidelines were less discriminative than the ESC guidelines (ACC/AHA C statistic 0.67 for men, 0.68 for women; ATP-III C statistic 0.67 for men, 0.69 for women; ESC C statistic 0.76 for men, 0.77 for women). All models overestimated the risk for events in each risk category. For example, using the ACC/AHA guidelines, predicted vs observed cumulative risk of hard ASCVD events was 21.5% vs 12.7% for men, and 11.6% vs 7.9% for women. In a relatively healthy, mostly white population such as this cohort, overestimation of CVD risk may result in more people being treated than necessary. 

A Multisite Randomized Controlled Trial of Brief Intervention to Reduce Drinking in the Trauma Care Setting: How Brief Is Brief?

Alcohol abuse is a common factor in trauma, and level 1 trauma centers are required to provide brief interventions to reduce alcohol use among patients with alcohol problems. However, the most effective structure and content of these “brief” interventions is unclear. In this randomized trial, 596 intentionally and unintentionally injured patients who screened positive for heavy drinking were assigned 1:1:1 to receive brief advice (average time 4.7 minutes), brief motivational intervention (BMI) (average time 22.5 minutes), or BMI and a telephone booster using personalized feedback (BMI+B) (average time 50.5 minutes) to study the effect on self-reported drinking rates at 3, 6, and 12 months. In intent-to-treat analysis, patients in the BMI+B group reported drinking 2.64 fewer drinks per week at 3 months and 2.31 fewer drinks/week at 6 months than the brief advice group (p=.01 and p=.02, respectively). They also reported 11% fewer heavy drinking days (p=.04) at 6 months and 2.34 fewer maximum number of drinks per day at 12 months (p=.02) than the brief advice group. However, contact time was a confounder, and all groups consumed less alcohol at 3 months and had fewer reported problems with alcohol at 6 and 12 months than at baseline. 

Multidisciplinary Diabetes Care with and without Bariatric Surgery in Overweight People: a Randomised Controlled Trial

It is well-established that bariatric surgery can improve or eliminate diabetes among obese patients, but the effect of bariatric surgery on glycemic control in overweight patients is unknown. In this small, single-center, open-label, randomized controlled trial, 51 patients in Melbourne, Australia, were assigned to either laparoscopic adjustable gastric band surgery and multidisciplinary diabetes care, or multidisciplinary diabetes care alone to study the effect on diabetes remission. Among the gastric band group, 52% achieved diabetes remission at 2 years, compared to 8% in the control group (difference in proportions 44%, p=0.0012). Diabetes remission was associated with weight loss of >8% bodyweight, which was more common among patients who underwent gastric banding (on average -11.5kg vs -1.6kg among patients in the control group. The authors postulate that the cost of gastric band surgery may be recouped after 5 years due to halving the annual cost of medical management for diabetes. 

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