Andrew Smith

A class of drugs known as PCSK9 inhibitors are approved to treat rare inherited conditions known as familial hypercholesterolemias. By inhibiting the enzyme encoded by the proprotein convertase subtilisin/kexin type 9 gene, these drugs can dramatically reduce cholesterol and significantly reduce cardiovascular events in patients with these inherited conditions.

Researchers have been investigating whether these drugs can also protect other patients at high risk for a cardiovascular event, including some whose low-density lipoprotein cholesterol (LDL-C) levels are well below currently recommended thresholds resulting from optimized statin therapy.

The first strong evidence arrived in March, and the answer appears to be yes.

Data from 3 large trials—the FOURIER trial of evolocumab (Repatha/Amgen) and the SPIRE-1 and SPIRE-2 trials of a discontinued experimental product called bococizumab (Pfizer)&mdash;indicate that patients with a history of cardiovascular events benefit significantly from dramatic LDL-C reductions associated with PCSK9 use, even when they begin with “low” cholesterol.

After a federal judge banned the sale of the only other approved drug in the class, alirocumab (Praluent/Sanofi, Regeneron), when Amgen successfully claimed that the product infringed on 2 of its patents, the US Court of Appeals in early February granted a stay of the controversial decision that would have seen Praluent pulled from the market. Would-be competitors are undergoing trials, but none are close to market.â€¨

The SPIRE trials provided indirect evidence to support using a PCSK9 inhibitor in combination with statin therapy, although collective analysis of the 2 trials found that bococizumab use was not associated with significant reductions in cardiovascular events. When investigators looked only at the higher-risk patients in the SPIRE-2 trial, however, and at patients in both trials who maintained a strong response to the drug, they found that patients who used bococizumab enjoyed significantly better outcomes than statin-only controls.

The FOURIER trial, moreover, provided strong, direct evidence to support supplemental treatment in patients with a history of atherosclerotic cardiovascular disease who used statins. It showed that the addition of evolocumab to statin therapy reduced the risk of a broad composite of cardiovascular outcomes by 15% among 27,564 such patients.

Researchers looking at the risk of myocardial infarction (MI), stroke, and cardiovascular death found that evolocumab reduced the risk risk by 20% overall and that reduction grew to 25% beyond the first year of treatment.

“I believe these data should change treatment protocols for high-risk patients,” said FOURIER lead investigator Marc S. Sabatine, MD, the Lewis Dexter, MD, Chair in Cardiovascular Medicine at Brigham and Women’s Hospital in Boston. “There is simply no medical reason why you would not use a treatment that reduces major cardiovascular outcomes by 25% while producing no significant adverse events,” he said.

Current indications from the FDA and current standards of care from specialty societies advocate the use of PCSK9 inhibitors mostly for the treatment of patients with heterozygous or homozygous familial hypercholesterolemia. But insurers appear to be balking at using PCSK9 for even those conditions because of wholesale prices that, according to a 

 article by Dhruv S. Kazi, MD, top $14,000 a year.

A pair of studies presented at the American College of Cardiology’s 66th Annual Scientific Sessions by Duke University’s Ann Marie Navar, MD, PhD, found that commercial payers and Medicare are rejecting about 80% of initial requests for evolocumab coverage.

Pressure for wider coverage could mount, however, if follow-up research demonstrates a significant reduction in cardiovascular death.

“Our evolocumab trial did not find a significant reduction in cardiovascular deaths, probably because of 2 reasons,” Sabatine said. “First, our follow-up only averaged a little over 2 years. Second, the proportion of cardiovascular deaths that are due to acute myocardial infarction and acute stroke are much lower now than in the past.”

Sabatine believes that 5-year evolocumab usage data would show a significant death reduction and the elimination of roughly 1 MI, death, or stroke for every 25 patients treated. That figure, he noted, is comparable with or lower than the number needed to treat findings in the trials that justified statin therapy in patients with average cholesterol levels as well as the trials that justified intensive statin therapy.

The FOURIER trial evaluated evolocumab in patients with a history of cardiovascular disease and LDL-C of ≥70 mg/dL. Investigators supplemented the regimens of those 27,564 patients with injections of either placebo or evolocumab. (Patients chose in advance between 140 mg every 2 weeks or 420 mg every month and received either the medication or the placebo injection on the preferred timetable.)

After a median follow-up of 2.2 years, 1344 patients receiving evolocumab (9.8%) and 1563 patients receiving placebo (11.3%) experienced cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (HR, 0.80; 95% CI, 0.73-0.88; 

 <.001). Patients receiving evolocumab, whose LDL-C fell from a median of 92 mg/dL at baseline to 30 mg/dL after 48 weeks of treatment, fared even better than patients receiving placebo on the secondary endpoint: a composite of cardiovascular death, MI, or stroke (HR, 0.80; 95% CI, 0.73- 0.88; 

Previous trials had shown that evolocumab and alirocumab could lower LDL-C levels by more than 50%, even in patients who were already using other medications. Other trials had shown improved outcomes when mean LDL-C levels fell from the recommended level of 100 mg/dL to 70 mg/ dL and in a subsequent trial, from 70 mg/dL to 54 mg/dL.

No previous trial, however, had demonstrated an association between subsequent reductions and further improvements to outcomes, but Sabatine and his colleagues noted in the 

that patients who began in the lowest quartile of LDL-C—patients whose mean levels fell from 70 mg/dL to just 22 mg/dL&mdash;saw a greater reduction in the risk of cardiovascular death, MI, or stroke (—22%) than those in the top quartile of LDL-C levels, whose mean levels fell from 126 mg/dL to 43 mg/ dL and whose risk for a cardiovascular event fell 17%. In other words, reducing LDL-C levels to just under a quarter of what has long been a “healthy” level seems to improve cardiovascular outcomes.

These findings were bolstered by the SPIRE trial findings that were also published, as a single article, in the March 24 issue of 

SPIRE-1 evaluated supplemental bococizumab in 16,817 patients with a history of cardiovascular events and LDL-C ≥70 mg/dL, while SPIRE-2 evaluated it in 10,621 patients with LDL-C ≥100 mg/dL. Most patients in both trials initially experienced large reductions in LDL-C, but the effect diminished over time in many patients, leading Pfizer to end the study early and suspend development.

The truncated data failed to show a significant reduction of cardiovascular events in either SPIRE-1 patients or in the combined study group. However, the incomplete study data showed significant benefits for the higher-risk SPIRE-2 patients, along with various subgroups of patients who had experienced and maintained the greatest LDL-C reductions.

Although the study was not exactly a success for bococizumab, it demonstrated a simple truth about LDL-C.

“Lower is better,” said lead study author Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital.

Ridker also believes the recent trials justify PCSK9 combination therapy in high-risk patients, but he doubts it will become the norm anytime soon.

“The first step is to ensure that all patients are initially on high-intensity statin therapy and are compliant with diet, exercise, and smoking cessation,” he said.

Patients who need further LDL-C reduction have options: ezetimibe, which costs about $80 a month, or a PCSK9 inhibitor.

“For now, cost issues are likely to determine that choice,” Ridker said. â—  

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Articles

Researchers have been investigating whether PCSK9 inhibitors can protect other patients at high risk for a cardiovascular event.

Using PCSK9 Inhibitors to Reduce Major Cardiovascular Outcomes 

Standard MRIs might reveal cognitive impairment in patients with multiple sclerosis (MS).

Retrospective analysis of magnetic resonance imaging (MRI) scans of 51 patients with MS has found that easily visible brain atrophy may serve as a biomarker for cognitive impairment.

The findings could help simplify the difficult task of evaluating whether (and how much) the disease has taken a toll on the mental abilities of newly diagnosed patients and in predicting which of those patients face the highest risk for cognitive degeneration going forward.

Investigators began with images of patients who had undergone comprehensive cognitive assessment at roughly the same time as their scans. They made simple linear measurements of hippocampi, bifrontal ventricular width, third ventricular width, and bicaudate width. They also measured the area of the anterior corpus callosum, mid corpus callosum and posterior corpus callosum.

The investigators then used Pearson's correlations to examine the relationship between these measurements and cognitive test results. They also compared MRI results of the sample’s cognitively-impaired patients and its cognitively-normal patients using Analysis of Covariance.

Bicaudate width and third ventricular width were both negatively correlated with cognitive test performance. Measures of corpus callosai, on the other hand, were positively correlated with cognitive test performance.

Indeed, after controlling for potential con founders, bicaudate span was significantly (and negatively) tied outcomes on measures of immediate recall. Measures of both anterior corpus callosai and posterior corpus callosai were significantly related to measures of verbal fluency, immediate recall and higher executive function. The size of anterior corpus callosai was also significantly associated to results on processing speed tests, while the size of middle corpus callosai was significantly related to tests of immediate recall and higher executive function.

“A biomarker that would help identify those at risk of cognitive impairment, or with only mild impairment, would be a useful tool for clinicians,” the study authors wrote. “This study presents data demonstrating that simple to apply MRI measures of atrophy may serve as biomarkers for cognitive impairment in persons with MS.”

A number of prior studies have reported connections between cognitive impairment and easily calculated results on magnetic transfer imaging (MTI). 

, for example, found a significant connection (p<0.05) between quantitative volumetric estimates of cerebral lesion load and neurologic impairment in 44 patients. 

 that appeared in the same year, in the same publication, found that lesion loads on proton density-weighted measurements derived from MTI scans were associated with cognitive decline in 30 different patients.

 found moderate correlations between results on a digit modalities test, a verbal fluency test and a spatial recall test and results from diffusion tensor—MRI scans used to measure lesion volume and brain volume.

Such specialized forms of MRI scans are not frequently used, however, so correlations between scan results and cognitive impairment are not widely applicable. A well-documented link between cognitive decline and results on the standard type of MRI scan that is often used to diagnose or evaluate MS would be much more practical, the authors of the new study wrote.

Developing easy to perform routine MRI measurements as potential surrogates for cognitive impairment in MS

MRI Scans Correlate Taste Loss and MS Lesions

MRI Could Be Used for Multiple Sclerosis Diagnostics

MRI Technique Can Differentiate Between Multiple Sclerosis and Neuromyelitis Optica

Standard MRIs might reveal cognitive impairment in MS patients.

MRI Scans May Detect Cognitive Impairment in Multiple Sclerosis

	A diminished sense of smell, common among multiple sclerosis (MS) patients, may be tied to disease severity.

A three-year-long study on 20 patients with MS indicates that roughly half of all patients with MS may have a reduced sense of smell and that olfactory impairment may be a marker for disease progression.

Investigators used a Taste Strip Test to measure gustatory discrimination, a Threshold Discrimination Identification test to measure subjective olfactory capacity and an EEG at the end of the study to objectively measure olfactory evoked potentials.

Sense of smell remained roughly unchanged over the study period. The baseline Threshold Discrimination Index test indicated that half of the cohort (10 patients) suffered hyposmia, while the final test returned the same results for 45% of the patients (nine patients). Sense of taste also remained roughly constant during the study period. The baseline test and the final test both found gustatory dysfunction in 20% of the cohort.

Overall, the patients in the study showed only mild disease activity and suffered an average of 0.3 ± 0.5 relapses during the study period. There was no significant correlation between their sense of taste and levels of disease activity, but olfactory function correlated inversely with the number of relapses that patients typically suffered over the three years (r = -0.5; p ≤ 0.05). There was also a significant connection between an impaired sense of taste and impaired sense of smell; 75% of patients who suffered the former problem also suffered the latter problem.

“Our previous study showed a correlation between a decreased olfactory bulb and olfactory brain volume and increased numbers and volumes of MS lesions in the olfactory brain of MS patients,” the study authors wrote. “These results further suggest a correlation between the olfactory function and disease activity in MS patients. Olfactory dysfunction in MS patients might be due to MS lesions or atrophy in the olfactory brain.”

The investigators used 48 Sniffin’ Sticks with a 16-stage dilution series of n-butanol to measure how well cohort members could smell. Patients tried to identify everyday odors such as “fish” or “coffee.” A score of less than 16 points was rated as anosmia, while up to 30.5 points was rated as hyposmia and a score above that was rated normosmia. The patients also estimated their smell function on a visual analogue scale ranging from 0 to 10 points. The 16-part tasting test used strips to evaluate the ability to discern sweet, sour, salty and bitter, each at four different concentrations.

As the authors of the new paper mentioned, this is not the first study to link multiple sclerosis with an impaired sense of smell. 

 reported demyelination in both the inferior frontal cortex and the olfactory bulb or tract of 70.6% of pathologically confirmed multiple sclerosis cases. Another four studies have noted significantly elevated rates of olfactory impairment among multiple sclerosis patients, although the reported percentage of patients suffering such problems ranged all the way from 

The authors of the new study, who believe they are the first to perform a longitudinal study on the sense of taste and smell of more than five patients with multiple sclerosis, speculated that the treatment taken by cohort members may explain why the cohort’s olfactory performance remained constant throughout the study period.

Longitudinal Testing of Olfactory and Gustatory Function in Patients with Multiple Sclerosis

Loss of sense of smell predicts more severe multiple sclerosis. 

Loss of Sense of Smell Predicts Worse Multiple Sclerosis

An analysis of Canadian patient data has found that people who sought emergency care for atrial fibrillation (AF) or atrial flutter were less likely to require hospital admission or a second emergency room visit when they received their initial treatment at emergency departments that handle many cases of AF.

Investigators tracked all 43,372 instances of patients aged 35 years or older seeking care for AF or atrial flutter from any of the 104 emergency departments in Alberta between 1999 and 2011. The investigators compared outcome data for cases treated in the province’s 11 high-volume emergency departments (those that treated 100 or more cases a year) and for cases treated in its 93 low-volume emergency departments.

Treatment at high-volume emergency departments was associated with lower rates of hospital admission (adjusted odds ratio [OR], 0.68; 95% confidence interval [CI], 0.64-0.72; p<0.001) and fewer returns to the emergency department within 90 days (OR, 0.81; 95% CI, 0.73-0.90; P<0.001).

Treatment at high-volume emergency departments was also associated with a greater likelihood of patients following up with specialists in both a 30-day period (OR, 1.81; 95% CI, 1.68-1.94; p<0.001) and a 90-day period (OR, 1.82; 95% CI, 1.76-2.03; p<0.001).

Even among patients who were admitted to the hospital after seeking emergency care, treatment at high-volume emergency departments was associated with fewer subsequent emergency department visits both in the next 30 days (OR, 0.37; 95% CI, 0.15-0.87; p= 0.02) and in the next 90 days (OR, 0.48; 95% CI, 0.26-0.89; p= 0.02).

There was, however, no difference in death rates between patients who sought care at high-volume and low-volume emergency departments.

“In the emergency department, higher volumes have been associated with lower in-hospital death in multiple conditions (e.g., pneumonia, heart failure, sepsis, stroke, respiratory failure, gastrointestinal hemorrhage and renal failure),” the study authors 

. “Using a comprehensive, reliable, population-based database for emergency department presentations, we identified familiarity based on the volume of patients seen annually as a factor to explain some of the practice variation observed in Alberta emergency departments with respect to the outcomes of patients with primary atrial fibrillation or flutter.”

The authors of the new study believe they are the first to explore the relationship between emergency department volume and outcomes in patients with atrial fibrillation and flutter. That said, they noted that many previous studies have found that greater experience treating a particular condition often leads to better outcomes.

The authors of the new study could not say exactly how AF care varied from high-volume to low-volume emergency departments, or even that it did vary. The databases mined for the study capture few details about case severity or treatment specifics. There are, of course, very specific guidelines for the treatment of AF, which theoretically should insure similar care everywhere, but the authors of the new study noted that previous research has found significant variation in real-world treatment patterns.

“For example,” they wrote, “rate control practices, decisions regarding prompt cardioversion (chemical vs electrical), specialist referrals and follow-up time vary according to age, sex, socio-economic status, location and hospital setting (e.g., rural vs urban). Emergency department management and follow-up vary, and outcomes could be improved.”

Emergency departments' experience matters in treating atrial fibrillation.