Primecuts – This Week In The Journals

November 21, 2016

Hamilton_StarBy Maria Sunseri, MD

Peer Reviewed

This week we saw America’s favorite musical deliver an unscripted yet heartfelt message at the end of the performance to audience member Vice President-Elect Mike Pence. And while President-Elect Donald Trump rushed to Twitter to reprimand the Hamilton cast’s message as harassment, the Indiana governor and inadvertent Planned Parenthood donor (albeit in name only) had only good things to say about the hit Broadway show. And while Americans and the medical world continue to navigate the post-election fallout, the USPSTF released new recommendations on the use of statins for primary prevention, expanding upon the 2013 ACC/AHA guidelines in potentially surprising ways.

USPSTF Recommendation Statement – Use of Statins for Primary Prevention of Adult Cardiovascular Disease

Cardiovascular disease (CVD), including coronary artery disease and cerebrovascular disease, remains the leading cause of morbidity and mortality in the United States, potentially leading to one in three deaths in adults.1 HMG-CoA reductase inhibitors, the popular lipid-lowering drug class known as statins, have been shown to both reduce levels of total cholesterol and LDL-C while having additional benefits through anti-inflammatory effects and plaque stabilization. The current model of risk estimation for CVD and potential statin benefit is based in the Pooled Cohort Equations from the 2013 ACC/AHA guidelines, but some feel that this model may overestimate actual risk in validation cohorts. For this reason, the USPSTF guidelines seek to offer expanded recommendations based on lipid screening for adults aged 40 and older without history of clinical CVD.

Summary of recommendations for patients without history of CVD:

  1. For adults aged 40-75 with >/= 1 CVD risk factor and a calculated 10-year CVD event risk of >/= 10%, initiate low-to-moderate intensity statin (Grade B)
  2. For adults aged 40-75 with >/=1 CVD risk factor and calculated 10-year event risk of 7.5-10%, discuss with patient and selectively offer low-to-moderate dose statin (Grade C)
  3. For adults aged 76 and older with no history of CVD, there is insufficient evidence to recommend statin initiation for primary prevention.

For these purposes, risk factors for CVD include dyslipidemia (LDL-C >130mg/dL or HDL-C <40mg/dL), diabetes, hypertension, and smoking. The 10-year risk is calculated using the ACC/AHA Pooled Cohort Equations. Of note, the USPSTF statement points out that the 10-year risk assessment is heavily weighted by age, and so many adults aged 65-75 may meet the recommended treatment threshold without additional risk factors of dyslipidemia, hypertension, diabetes, or smoking. As no trial has evaluated statin benefit in this age group for patients without CVD risk factors, the USPSTF recommends using shared decision making to discuss the risks and benefits of initiating a statin inthis population. The task force also reported insufficient evidence to justify screening for dyslipidemia in adults below age 40. The statement also comments on use of high-dose statins for primary prevention, stating that the choice of intensity should be left to shared decision-making, given the limited data comparing benefit to harm when high-intensity statins are used in primary prevention populations.

Finally, many have questioned the utility of evaluating CVD risk factors in addition to using a risk calculator, and some have questioned why the USPSTF utilizes a different cutoff for treatment than the prior ACC/AHA guidelines. Until further research compares the two strategies, it will be left to individual providers and their patients to determine the best tool for starting statin therapy in primary prevention populations.

Comparing Risk of Hyperkalemia from Sacubitril/Valsartan Versus Enalapril

There have been numerous studies suggesting that mineralocorticoid receptor antagonists (MRAs) can reduce the risk of death or hospitalization for patients with symptomatic heart failure and reduced ejection fraction (HFrEF). Current guidelines therefore recommend adding an MRA for patients who remain symptomatic despite treatment with beta-blockers and inhibitors of the renin-angiotensin-aldosterone system (RAAS). Despite this, providers are often limited by the heightened risk of hyperkalemia when an MRA is combined with a RAAS inhibitor.

In this week’s JAMA, Desai et al revisit the PARADIGM-HF trial, in which treatment with the novel angiotensin receptor/neprolysin inhibitor (ARNI) sacubitril/valsartan was associated with reduced rates of death and hospitalization for heart failure patients when compared to enalapril. For this secondary analysis, Desai and colleagues specifically examined the risk of hyperkalemia among PARADIGM-HF patients treated with an MRA.2 The PARADIGM-HF trial was a randomized, double blind, prospective comparison of sacubitril/valsartan and enalapril among patients with NYHA class II-IV heart failure and a left ventricular ejection fraction of 40% or less. The addition of MRAs was left to the discretion of the investigators, but was encouraged if tolerated. In both groups, more patients were on an MRA at baseline when enrolled in the trial (2400 of 4212 patients assigned to enalapril (57%); 2271 of 4187 patients assigned to sacubitril/valsartan (54.2%)). Overall, the incidence of hyperkalemia (K > 5.5 mEq/L) and severe hyperkalemia (K > 6.0 mEq/L) were significantly higher among patients treated with an MRA (incidence of hyperkalemia: 10 vs 7.3 per 100 patient-years, HR 1.33; severe hyperkalemia: 2.7 vs 2.0 per 100 patient-years, HR 1.35). When compared between groups, rates of hyperkalemia were similar between patients assigned to sacubitril/valsartan and those assigned to enalapril. Severe hyperkalemia, however, was significantly more common in patients assigned to enalapril (3.1 vs 2.2 per 100 patient-years, HR 1.37). This increased risk of severe hyperkalemia remained significant when patients who initiated MRA therapy during the trial were included in the comparison. The authors suggest that based on these data, more patients could benefit by substituting sacubitril/valsartan for an ACE inhibitor or ARB. Limitations of this study include that randomization in PARADIGM-HF was not stratified by baseline MRA use, opening the door for potential confounding from baseline risk for hyperkalemia. Further, patients with chronic kidney disease were excluded, and rates of hyperkalemia in this study may underestimate those seen in clinical practice given the association between CKD and heart failure. That said, this new data about hyperkalemia is an important consideration for further research given the building evidence in support of novel therapy with ARNIs for patients with heart failure.

Reducing Albuminuria in Diabetic Nephropathy with Phosphodiesterase Inhibitors

Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in the Western world, and it affects one-third of all diabetic patients. Progression from nephropathy to ESRD is highest in patients with macroalbuminuria, and while therapy with ACE inhibitors or ARBs has been shown to reduce albuminuria and slow progression of renal disease, the residual degree of albuminuria still correlates with risk of progression to ESRD. Attempts have been made to mitigate this risk by combining ACE inhibitors or ARBs with a direct renin inhibitor (aliskiren in the ALTITUDE trial) or by combining treatment with both an ACE inhibitor and an ARB (NEPHRON-D trial). However, these trials were associated with worse patient outcomes, including hyperkalemia, strokes, and acute worsening of renal function.3

Scheele and colleagues studied the addition of phosphodiesterase inhibition in this week’s Journal of the American Society of Nephrology. Utilizing preclinical data that phosphodiesterase type 5 (PDE5) inhibition is renoprotective, the investigators conducted a multinational, multicenter, randomized, double-blind placebo-controlled trial to test the effects of a selective long-acting PDE5 inhibitor in subjects with type-2 diabetes and overt nephropathy already on ACE inhibitor or ARB therapy. The drug, known as PF-00489791, was found to significantly reduce albuminuria, with a 15.4% reduction from baseline in urinary albumin to creatinine ratio (UACR) at 12 weeks. This was compared to the placebo group who instead had a 0.4% increase in UACR over the same period. The trial had a major limitation in that sodium intake and excretion were not monitored during the trial. Further studies are required that include strict sodium monitoring, given the data that sodium intake reduction has meaningful impact on reducing albuminuria, and could act as a significant confounding factor if not controlled. That said, the significant improvement in albuminuria and minimal side-effect profile from long-acting PDE5 inhibitors offers a promising addition to the current standard of care in slowing progression to ESRD in diabetic nephropathy.

Evaluating Ustekinumab in Patients with Crohn’s Disease 

Crohn’s disease, a chronic inflammatory bowel disease, is commonly treated with glucocorticoids, immunosuppressants, tumor necrosis factor (TNF) antagonists, or integrin inhibitors. These medications have serious side effects including increased risk of infection and cancer. Ustekinumab, a monoclonal antibody to interleukin-12 and interleukin-23, has been used in treatment of psoriasis and psoriatic arthritis without increased risk of adverse events.4 In this week’s NEJM, Feagan et al presented a phase 3 trial investigating induction and maintenance therapy in patients with Crohn’s disease.

This trial consisted of two eight-week induction trials (UNITI-1 and UNITI-2) as well as one 44-week maintenance trial (IM-UNITI). These multicenter, multinational trials were double-blind and placebo-controlled. Patients in the induction trials were randomly assigned to placebo or ustekinumab; those who responded to the experimental drug were able to enroll in the maintenance trial, and were again randomized to placebo or ustekinumab therapy. In both UNITI-1 and UNITI-2, patients had significant improvement in symptoms at six weeks when treated with ustekinumab at either 130mg or 6mg per kilogram when compared to placebo (UNITI-1: 34.3%/33.7% vs 21.5% placebo; UNITI-2: 51.7%/55.5% vs 28.7% placebo). In each induction trial, both doses of ustekinumab were associated with greater reductions in C-reactive protein and fecal calprotectin than placebo. In IM-UNITI, there were significantly more patients in remission at week 44 receiving ustekinumab than placebo, regardless of drug dosing schedule (treatment every 8 weeks: 53.1% remission; treatment every 12 weeks: 48.8% remission; placebo: 35.9% remission). Rates of adverse events were similar between treatment and placebo groups. While this trial is limited by the subjective nature of the primary outcomes, the objective decrease in CRP and fecal calprotectin offer promise of reducing inflammation in patients with Crohn’s disease. More long-term data is needed to compare ustekinumab to the current standard of care, but this drug may be a promising alternative to those who cannot tolerate conventional therapy due to adverse drug effects.

Mini Cuts

A randomized, multicenter, double-blind, noninferiority trial (the PRECISION trial) investigated patients taking daily NSAIDs for arthritis pain in order to determine relative safety of the selective COX-2 inhibitor celecoxib. Investigators found that cardiovascular risk associated with celecoxib is not greater than that from the nonselective NSAIDs ibuprofen and naproxen. In fact, celecoxib was associated with fewer cardiovascular events than its nonselective counterparts.5

A single-center retrospective case-control study in Chest examined consecutive patients with nonventilated hospital-acquired pneumonia (NVHAP) and to investigate for causative pathogens. While the majority of cases were pathogen-negative (56.3%), respiratory viruses were identified in 24.1% of affected patients, as compared to gram-negative and gram-positive bacteria being identified in 14.4% and 11.5%, respectively.6

Investigators working with the National Drug Abuse Treatment Clinical Trials Network developed a new screening tool for commonly used substances that could easily fit into the primary care workflow. This tool, known as the Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS) tool, was tested in a multisite study of five adult primary care clinics. The TAPS tool identified problematic tobacco use with a 93% sensitivity and 87% specificity, and problematic alcohol use with 74% sensitivity and 79% specificity.  For illicit and prescription drugs, sensitivity ranged from 82% for marijuana to 63% for seditives.7

Dr. Maria Sunseri is a resident at NYU Langone Medical Center

Peer reviewed by Dana Zalkin, 2nd year resident internal medicine at NYU Langone Medical Center

Image courtesy of Wikimedia Commons


  1. US Preventive Services Task Force. Statin Use for the Primary Prevention of Cardiovascular Disease in AdultsUS Preventive Services Task Force Recommendation Statement. JAMA.2016;316(19):1997-2007. doi:10.1001/jama.2016.15450
  2. Desai AS, Vardeny O, Claggett B, McMurray JJV, Packer M, Swedberg K, Rouleau JL, Zile MR, Lefkowitz M, Shi V, Solomon SD. Reduced Risk of Hyperkalemia During Treatment of Heart Failure With Mineralocorticoid Receptor Antagonists by Use of Sacubitril/Valsartan Compared With EnalaprilA Secondary Analysis of the PARADIGM-HF Trial. JAMA Cardiol.Published online November 14, 2016. doi:10.1001/jamacardio.2016.4733
  3. Scheele W, Diamond S, Gale J, et al. Phosphodiesterase Type 5 Inhibition Reduces Albuminuria in Subjects with Overt Diabetic Nephropathy. J Am Soc Nephrol.2016;27(11):3459-3468.
  4. Feagan BG, Sandborn WJ, Gasnick C, et al. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med 2016; 375:1946-1960. November 17, 2016. DOI: 10.1056/NEJMoa1602773
  5. Nissen SE, Yeomans ND, Soloman DH, et al. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for arthritis. N Engl J Med 2016 accessed November 13, 2016. DOI: 10.1056/NEJMoa1611593
  6. Micek ST, Chew B, Hampton N, Kollef MH. A Case-Control Study Assessing The Impact Of Nonventilated Hospital-Acquired Pneumonia On Patient Outcomes. Chest. 2016;150(5):1008-1014. doi:10.1016/j.chest.2016.04.009.
  7. McNeely J, Wu L, Subramaniam G, Sharma G, Cathers LA, Svikis D, et al. Performance of the Tobacco, Alcohol, Prescription Medication, and Other Substance Use (TAPS) Tool for Substance Use Screening in Primary Care Patients. Ann Intern Med. 2016;165:690-699. doi: 10.7326/M16-0317