Primecuts – This Week in the Journals

May 8, 2017

HALLANDALE BEACH, FL - APRIL 01:  #4 Always Dreaming (FL) wth jockey John Velazquez on board, wins the Xpressbet Florida Derby (Grade I) at Gulfstream Park on April 01, 2017 in Hallandale Beach, Florida. (Photo by Liz Lamont/Eclipse Sportswire/Getty Images)

HALLANDALE BEACH, FL – APRIL 01: #4 Always Dreaming (FL) wth jockey John Velazquez on board, wins the Xpressbet Florida Derby (Grade I) at Gulfstream Park on April 01, 2017 in Hallandale Beach, Florida. (Photo by Liz Lamont/Eclipse Sportswire/Getty Images)

By Alicia Cowley, MD, MBA

Peer Reviewed

This past Thursday, the American Health Care Act narrowly survived a full vote in the House. The American College of Physicians, the American Medical Association, the American Academy of Family Physicians, and at least a dozen other health care organizations have released statements imploring the Senate to dismiss this bill that reduces coverage and protection for our country’s most vulnerable patients. This event represents one of the rare instances in which major associations representing doctors, hospitals, insurers, and seniors have all been in agreement.

Meanwhile, on the other side of the Atlantic, the centrist candidate (and new president-elect) Emmanuel Macron was hit by a hacking attack that resulted in 9GB of internal emails and documents a mere 24 hours before facing Marine Le Pen, the far-right candidate of the National Front, at the ballot box. Since neither candidate represents the two parties that have traditionally dominated French politics, this election cycle speaks to the divisions within France as well as Europe as a whole regarding immigration as well as participation in the European Union.

As we wait with bated breath regarding the aforementioned votes, the news also buzzes with lighter stories such as Always Dreaming’s victory at the Kentucky Derby and the Federal Communications Commision’s investigation of Stephen Colbert’s controversial Trump joke. As healthcare has its moment at center stage, here are some of the latest updates in clinical care.

Clinical Outcomes of Metformin Use in Populations with Chronic Kidney Disease, Congestive Heart Failure, or Chronic Liver Disease

Phenformin, a binguanide previously used for glycemic control, was withdrawn in the late 1970s due to its association with often fatal lactic acidosis in patients with renal impairment. As a related biguanide, metformin came with a boxed warning regarding the risk of lactic acidosis when it was first approved by the US Food and Drug Administration (FDA) in 1994, especially in the setting of chronic kidney disease (CKD). Furthermore, it came with a recommended caution in patients whose comorbid conditions may promote lactate accumulation (e.g. congestive heart failure (CHF) and chronic liver disease (CLD)). The literature suggests that there actually is no clear link between metformin use and lactic acidosis [1].

More recently, the FDA has dialed back its strict boxed warning. In the last decade, the FDA removed chronic, stable CHF as a contraindication to metformin use. In April 2016, the FDA modified its exclusion criteria for CKD patients by switching its definition of renal impairment from a creatinine-based one to a more inclusive one based on estimated glomerular filtration rate. With metformin’s expanding use in patients with historical contraindications or precautions, it is important to promote informed prescribing practices among providers.

In a systematic review and meta-analysis, Crowley and colleagues explored the outcomes of metformin use in patients with type 2 diabetes and moderate to severe CKD (with eGFR as low as 30 mL/min/1.73 m2), CHF, or CLD with hepatic impairment [2]. In these patients, metformin was associated with reduced all-cause mortality, fewer heart failure readmissions in patients with CKD or CHF, and a lower hypoglycemia rate among those with moderate CKD. Although quite favorable, these results are flawed in that available results were observational studies with high risk for bias given the possibility of unaccounted-for between-group differences in disease severity, the inability to capture potential differences in hazard over time, and post-baseline medication changes when looking at patients with metformin use at baseline versus comparator patients. Despite these limitations, metformin is a safe, effective, and inexpensive first-line option for patients with type 2 diabetes. In adults with type 2 diabetes and moderate to severe CKD, CHF, or CLD with hepatic impairments, metformin is associated with improvements in key clinical outcomes, including all-cause mortality and hospital readmission.

Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients

Although Pfizer has discontinued its global clinical development program for bococizumab, its cholesterol-lowering proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor, the clinical information put forth by Ridker and colleagues’ Studies of PCSK9 Inhibition and the Reduction of Vascular Events (SPIRE) program still highlight the evolving treatment and market landscape for lipid-lowering agents [3]. Ridker et al conducted two parallel, multinational lipid-lowering trials enrolling a total of 27,438 high-risk patients (mean age 62.9 years, 29.6% women, LDL-C 94 mg/dL in SPIRE-1 and 135 mg/dL in SPIRE-2) who were treated with maximally tolerated statin doses (92.9% on any statin dose, 84.5% on high-intensity statin) as well as 150 mg of bococizumab or placebo subcutaneously every two weeks and were followed for up to one year.

The primary outcome included incidence of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for unstable angina requiring revascularization. In SPIRE-2, bococizumab reduced cardiovascular events in patients with higher baseline LDL levels (>100 mg/dL) who were followed for a longer duration (median 12 months) (hazard ratio [HR] of 0.79, 95% confidence interval [CI] 0.65 to 0.97, P=0.02). However, the PCSK9 inhibitor did not demonstrate any effect on cardiovascular events in SPIRE-1 (HR 0.99, 95% CI 0.80 to 1.22; P=0.94), which included patients with lower baseline LDL levels (>70 mg/dL) who were followed for a shorter duration (median 7 months). Antidrug antibodies developed in almost half (48%) of the patients who received bococizumab and neutralizing antibodies developed in 29%. These antibodies are thought to have substantially attenuated LDL-cholesterol lowering over time.

These antidrug antibodies appear to be limited to bococizumab, a partial murine-based agent, and is not an issue with the fully human monoclonal antibodies evolocumab (Repatha, Amgen) and alirocumab (Praluent, Sanofi/Regeneron). Last month, new data on alirocumab published in the New England Journal of Medicine, shows that antidrug antibodies develop in just 5.1% of patients (vs 1.0% of controls) and neutralizing antibodies in 1.3% [4]. Amgen recently completed a  large cardiovascular-outcomes study, FOURIER, to study the effects of evolocumab on the same primary endpoints explored by the SPIRE program. In just shy of a year, evolocumab was able to reduce LDL cholesterol levels by 59% compared to placebo (from a median baseline value of 92 mg/dL to 30 mg/dL, P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary point already defined by SPIRE (1344 patients [9.8%] vs 1563 patients [11.3%]; hazard ratio 0.85; 95% CI 0.79 to 0.92; P<0.01). These results were consistent across subgroups, including those patients with the lowest quartile for baseline LDL cholesterol (medial 74 mg/dL), suggesting that patients with atherosclerotic cardiovascular disease (ASCVD) may benefit from lowering LDL below current targets.

Despite the promise that PCSK9 inhibitors may have for atherosclerotic cardiovascular disease prevention, their annual cost does not meet cost-effective thresholds [6]. According to Kazi et al’s insightful simulation model of US adults aged 35 to 94 years, adding PCSK9 inhibitor therapy to current statin regimens for patients with heterozygous familial hypercholesterolemia or ASCVD is estimated to cost $423,000 per quality-adjusted life-year (QALY) gained and could increase US health care costs by $565 billion over 5 years. In contrast, adding ezetimibe is almost three times less expensive at $152,000 per QALY and starting statins in all high-risk patients who are not currently on statins and are statin-tolerant is estimated to save $12 billion on a national scale.

Stroke in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic, systemic inflammatory disease that has been associated with increased risk of cardiovascular disease [7]. Although stroke has previously been studied as a composite endpoint in conjunction with cardiovascular disease, a group at the Karolinska Institute recognized that stroke is an important cause of morbidity and mortality in SLE that warranted its own investigation [8]. The group studied 3,390 SLE adult patients from the Swedish National Patient Register from 2003 to 2013, matched by age, sex, and residential county to 16,730 non-SLE controls obtained from the Total Population Register.

Compared to the general population, individuals with SLE had a twofold-increased rate of ischemic stroke (HR 2.2, 95% CI 1.7 to 2.8). The HR for intracerebral hemorrhage was 1.4 (95% CI 0.7 to 2.8). When further stratifying the data, the highest HRs were for females and individuals less than 50 years old. The rate of ischemic stroke was highest in the first year of follow-up (HR 3.7, 95% CI 2.1 to 6.5). Although this study has an impressive body of long-term data for a large population that spans both inpatient and outpatient settings, it does recognize its limitations, especially in regards to possible misclassification of SLE and stroke. The date of the second SLE-coded visit was used as the date of incident disease, which can result in misclassification of time to diagnosis of SLE as well as the exclusion of individuals who experienced a stroke soon after their first SLE diagnosis but before a second SLE diagnosis in a non-primary care setting was given. In other words, requiring specialist visits to confirm SLE minimized SLE misclassification but could have resulted in missed early strokes. These missed cases could lead to an underestimation of the stroke risk in the first year after SLE diagnosis.

Regardless of these limitations, the data speaks for itself and first encounters with SLE patients present an opportunity for primary care physicians and rheumatologists to intervene. Furthermore, studies such as this may promote the development of an SLE-specific risk score and evidence-based guidelines for stroke prevention.

Clinical Quality and the Patient-Centered Medical Home

The Patient-Centered Medical Home (PCMH) is a health care delivery model whereby patient treatment is coordinated through his or her primary care physician. According to the Agency for Healthcare Research and Quality (AHRQ), the medical home is a centralized setting that supports the following five functions: comprehensive care, patient-centered, coordinated care, accessible services, as well as quality and safety [9]. PCMH accreditation is a signal to payers, policymakers, and patients that a practice is committed to aligning patient preferences with payer and provider capabilities. In the near future, Medicare will likely use PCMH accreditation to award bonuses through its future value-based payment programs.

There are legitimate concerns regarding accredited practices’ sustainable commitment to PCMH efforts. There is a fear that accreditation consists of just checking off boxes. For example, in a capitation payment model, payers need reliable, external validation to justify their bonuses. More importantly, patients and their families want to know whether PCMH practices actually focus on delivering high quality, patient-centered, coordinated care for every patient.

Regardless of whether one works in a PCMH model or not, there is no denying that the aforementioned functions should improve patient care and it would be helpful to find out which are the biggest drivers of improved clinical quality. A study published in JAMA conducted a patient-level observational study through the Veterans Health Administration (VHA) to gauge clinic-level PCMH implementation through the VHA’s own PCMH initiative, the Patient Aligned Care Team (PACT) program [10]. PACT encompasses eight core domains: access, continuity, care coordination, comprehensiveness, self-management support, patient-centered care and communication, shared decision-making, and team-based care.

The group assessed clinic-level PCMH implementation in 909 clinics using the PACT Implementation Progress Index (Pi2). When modeling the association between quartile of Pi2 component and 48 clinical quality indicators, it was no surprise that higher scores on each of Pi2’s eight components was associated with better performance in clinical quality indicators. Out of those eight domains, the strongest drivers of quality are care coordination, access, continuity, and communication. High levels of care coordination resulted in clinics having significantly better quality scores on 33 of 48 (69%) quality measures compared with lower-performing clinics. Comparable results were seen when it comes to improved access (32 [67%]), continuity (29 [60%]), and communication (25 [52%]).

By extrapolating these results to the entire VHA primary care population (5.4 million patients), it is estimated that 310,468 additional high-quality services could have been delivered if all clinics performed equally well as the high-quartile clinics in regards to care coordination. Similar improvements in quality metrics are estimated to occur with better access (n= 258,999), continuity (n=253,816), and communication (n=285,193). As with any associational study, these results can not be used to generate a conclusion that invokes causation. That being said, this insight can help residency programs who are implementing PCMH models in their teaching clinics, which are often resource-constrained entities in underserved communities, focus their efforts on the highest yield domains first.


There is mounting evidence surrounding the role of gut microbial dysbacteriosis in the pathogenesis and perpetuation of inflammatory bowel disease (IBD). Oral iron treatment has long been the standard intervention for iron deficiency anemia in patients with IBD given its safety profile, low cost, and convenient route of administration, A new study in Gut suggests that high concentrations of luminal iron affect gut microbiota and fecal metabolites, especially in patients with Crohn’s disease who are more prone to iron replacement therapy-induced shifts [11]. Future practices may turn to intravenous iron therapy as first-line therapy for anemic Crohn’s disease patients with unstable microbiota.

As Bhattacharjee and colleagues at the University of Chicago review the evolving definition of sepsis, we gain a better understanding of how sepsis was traditionally monitored on the medicine wards (SIRS) and the advancements that we are striving for to achieve improved specificity [12]. Interestingly, we catch a glimpse of the data behind automatic electronic medical record (EMR)-based sepsis alerts – in one interventional study, a triggered alert resulted in a significant decrease in median time to any sepsis-related intervention by a median difference of 3.5 hours (P=0.02) [13]. Future directions point to procalcitonin as a promising biomarker as well as better application of machine learning to our EMR data.

How many times have we been frustrated by medication non-compliance, especially when patients say they just forgot to take their pills? The REMIND trial looked at the effect of three low-cost reminder devices on medication adherence [14]. Participants included individuals ages of 18 and 64 taking one to three oral medications with suboptimal adherence to all their prescribed medications (medication possession ratio 30% to 80% at baseline) and stratification based on medication categories (cardiovascular or other non-depression chronic conditions versus antidepressants) as well as dosing schedule. Unfortunately, there was no statistical difference in adherence between those in the control group and those who received a reminder device (standard pillbox, digital timer cap, or pill bottle strip with toggles). Looks like it’s back to the drawing board to come up with more effective interventions.

Dr. Alicia Cowley is a resident at NYU Langone Medical Center

Peer reviewed by Kevin Hauck, MD, internal medicine, NYU Langone Medical Center

Image courtesy of Horse Racing Nation:


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  2. Crowley MJ, Diamantidis CJ, McDuffie JR, Cameron CB, Stanifer JW, Mock CK, et al. Clinical Outcomes of Metformin Use in Populations With Chronic Kidney Disease, Congestive Heart Failure, or Chronic Liver Disease: A Systematic Review. Ann Intern Med. 2017;166:191-200.
  3. Ridker PM, et al. Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients. N Engl J Med 2017;376:1527-1539.
  4. Roth EM, et al. Antidrug Antibodies in Patients Treated with Alirocumab. N Engl J Med 2017;376:1589-1590.
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