Purpose of review

The omega-3 fatty acids (n3-FAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have recently undergone testing for their ability to reduce residual cardiovascular (CV) risk among statin-treated subjects. The outcome trials have yielded highly inconsistent results, perhaps attributable to variations in dosage, formulation, and composition. In particular, CV trials using icosapent ethyl (IPE), a highly purified ethyl ester of EPA, reproducibly reduced CV events and progression of atherosclerosis compared with mixed EPA/DHA treatments. This review summarizes the mechanistic evidence for differences among n3-FAs on the development and manifestations of atherothrombotic disease.

Recent findings

Large randomized clinical trials with n3-FAs have produced discordant outcomes despite similar patient profiles, doses, and triglyceride (TG)-lowering effects. A large, randomized trial with IPE, a prescription EPA only formulation, showed robust reduction in CV events in statin treated patients in a manner proportional to achieved blood EPA concentrations. Multiple trials using mixed EPA/DHA formulations have not shown such benefits, despite similar TG lowering. These inconsistencies have inspired investigations into mechanistic differences among n3-FAs, as EPA and DHA have distinct membrane interactions, metabolic products, effects on cholesterol efflux, antioxidant properties, and tissue distribution. EPA maintains normal membrane cholesterol distribution, enhances endothelial function, and in combination with statins improves features implicated in plaque stability and reduces lipid content of plaques. Insights into reductions in residual CV risk have emerged from clinical trials using different formulations of n3-FAs. Among high-risk patients on contemporary care, mixed n3-FA formulations showed no reduction in CV events. The distinct benefits of IPE in multiple trials may arise from pleiotropic actions that correlate with on-treatment EPA levels beyond TG-lowering. These effects include altered platelet function, inflammation, cholesterol distribution, and endothelial dysfunction. Elucidating such mechanisms of vascular protection for EPA may lead to new interventions for atherosclerosis, a disease that continues to expand worldwide.

Cardiac rehabilitation (CR) referral is recommended for eligible patients, regardless of sex or race. It is unclear whether inequality in CR referral practices was associated with patients' long-term survival. We linked the American Heart Association Get With The Guidelines Coronary Artery Disease registry with Medicare claims data for 48 993 coronary artery disease patients from 365 hospitals across the United States between 2003 and 2009. We used generalized estimation equations to estimate the association between CR referral and mortality accounting for clustering within hospitals. Between 2003 and 2009, only 40% of eligible patients received CR referrals. Females were 12% less likely to receive CR referral compared with males. Black, Hispanic, and Asian patients were 20%, 36%, and 50% less likely, respectively, to receive CR referral than white patients. CR referral was associated with 40% lower 3-year all-cause mortality. Women and minorities who received CR referral at hospital discharge had significantly lower mortality compared with those who did not (odds ratios=0.61 [95% confidence interval, 0.56-0.66] for women, 0.75 [95% confidence interval, 0.63-0.88] for black, 0.62 [95% confidence interval, 0.50-0.79] for Hispanic, and 0.63 [95% confidence interval, 0.46-0.85] for Asian patients). Seven percent of the black versus white mortality gap could potentially be reduced by equitable CR referral. CR referral rates at hospital discharge remained low. Gaps in receiving CR referral at hospital discharge were large for women and minorities, and the mortality gap could potentially be reduced through elimination of inequality in CR referral.

Aims

Icosapent ethyl (IPE) significantly reduced ischaemic events in statin-treated patients with atherosclerosis or diabetes and elevated triglycerides in REDUCE-IT, including large reductions in myocardial infarction and elective, urgent, and emergent coronary revascularization. However, the mechanisms driving this clinical benefit are not fully known. The EVAPORATE trial demonstrated that IPE significantly reduced plaque burden. No study to date has assessed the impact of IPE on coronary physiology. Fractional flow reserve (FFR) derived from coronary computed tomography angiography (CTA) data sets (FFRCT) applies computational fluid dynamics to calculate FFR values in epicardial coronary arteries. Our objective was to assess the impact of IPE on coronary physiology assessed by FFRCT using imaging data from EVAPORATE.

Methods and results

A total of 47 patients and of 507 coronary lesions at baseline, 9 months, and 18 months with coronary CTA and FFRCT were studied in a blinded core lab. The pre-specified primary endpoint was the FFRCT value in the distal coronary segment from baseline to follow-up in the most diseased vessel per patient using IPE compared with placebo. The pre-specified secondary endpoint was the change in translesional FFRCT (ΔFFRCT) across the most severe (minimum 30% diameter stenosis) coronary lesion per vessel. Baseline FFRCT was similar for IPE compared with placebo (0.83 ± 0.08 vs. 0.84 ± 0.08, P = 0.55). There was significant improvement in the primary endpoint, as IPE improved mean distal segment FFRCT at 9- and 18-month follow-up compared with placebo (0.01 ± 0.05 vs. -0.05 ± 0.09, P = 0.02, and -0.01 ± 0.09 vs. -0.09 ± 0.12, P = 0.03, respectively). ΔFFRCT in 140 coronary lesions was improved, although not statistically significant, with IPE compared with placebo (-0.06 ± 0.08 vs. -0.09 ± 0.1, P = 0.054).

Conclusion

Icosapent ethyl demonstrated significant benefits in coronary physiology compared with placebo. This early and sustained improvement in FFRCT at 9- and 18-month follow-up provides mechanistic insight into the clinical benefit observed in the REDUCE-IT trial. Furthermore, this is the first assessment of FFRCT to determine drug effect.

Background

Hyperglycemia has been associated with adverse outcomes in patients with acute ischemic stroke (AIS) and may influence outcomes after tissue plasminogen activator (tPA). We sought to analyze the association of acute and chronic hyperglycemia on clinical outcomes in tPA-treated patients.

Methods and results

We identified 58 265 AIS patients from 1408 sites who received tPA from 2009 to 2013 in Get With The Guidelines-Stroke. Acute hyperglycemia at admission was defined as a plasma glucose level >140 mg/dL. Chronic hyperglycemia was defined by plasma glycosylated hemoglobin (HbA1c) >6.5%. Post-tPA outcomes were analyzed using logistic regression. Blood glucose >140 mg/dL and HbA1c >6.5 were associated with worse clinical outcomes (symptomatic intracranial hemorrhage [sICH], life-threatening hemorrhage, and in-hospital mortality and length of stay) in diabetic and nondiabetic patients. Among patients with documented history of diabetes, increasing admission glucose up to 200 mg/dL was associated with increased adjusted odds ratio (aOR) of in-hospital mortality (aOR, 1.07) and sICH (aOR, 1.05) per 10 mg/dL increase in blood glucose. Increasing HbA1C to 8% was associated with increased odds of in-hospital mortality (aOR, 1.19) and sICH (aOR, 1.16) per 1% increase in HbA1c. Similar findings were observed in patients without a documented history of diabetes. There was no further increase in poor outcomes above the blood glucose level of 200 mg/dL or HbA1c >8.

Conclusion

Acute and chronic hyperglycemia are both associated with increased mortality and worse clinical outcomes in AIS patients treated with tPA. Controlled trials are needed to determine whether acute correction of hyperglycemia can improve outcomes after thrombolysis.

Background

Sharing of patient-level clinical trial data has been widely endorsed. Little is known about how extensively these data have been used for cardiometabolic diseases. We sought to evaluate the availability and use of shared data from cardiometabolic clinical trials.

Methods

We extracted data from ClinicalStudyDataRequest.com, a large, multisponsor data-sharing platform hosting individual patient-level data from completed studies sponsored by 13 pharmaceutical companies.

Results

From January 2013 to May 2017, the platform had data from 3374 clinical trials, of which 537 (16%) evaluated cardiometabolic therapeutics (phase 1, 36%; phase 2, 17%; phase 2/3, 1%; phase 3, 42%; phase 4, 4%). They covered 74 therapies and 398 925 patients. Diabetes mellitus (60%) and hypertension (15%) were the most common study topics. Median time from study completion to data availability was 79 months. As of May 2017, ClinicalStudyDataRequest.com had received 318 submitted proposals, of which 163 had signed data-sharing agreements. Thirty of these proposals were related to cardiometabolic therapies and requested data from 79 unique studies (15% of all trials, 29% of phase 3/4 trials). Most (96%) data requesters of cardiometabolic clinical trial data were from academic centers in North America and Western Europe, and half the proposals were unfunded. Most proposals were for secondary hypothesis-generating questions, with only 1 proposed reanalysis of the original study primary hypothesis. To date, 3 peer-reviewed articles have been published after a median of 19 months (9-32 months) from the data-sharing agreement.

Conclusions

Despite availability of data from >500 cardiometabolic trials in a multisponsor data-sharing platform, only 15% of these trials and 29% of phase 3/4 trials have been accessed by investigators thus far, and a negligible minority of analyses have reached publication.

Background

Heart failure (HF) is the leading cause of morbidity and mortality in the United States. Despite advancement in the management of HF, outcomes remain suboptimal, particularly among the uninsured. In 2014, the Affordable Care Act expanded Medicaid eligibility, and millions of low-income adults gained insurance. Little is known about Medicaid expansion's effect on inpatient HF care.

Methods and results

We used the American Heart Association's Get With The Guidelines-Heart Failure registry to assess changes in inpatient care quality and outcomes among low-income patients (<65 years old) hospitalized for HF after Medicaid expansion, in expansion, and nonexpansion states. Patients were classified as low-income if covered by Medicaid, uninsured, or missing insurance. Expansion states were those that implemented expansion in 2014. Piecewise logistic multivariable regression models were constructed to track quarterly trends of quality and outcome measures in the pre (January 1, 2010-December 31, 2013) and postexpansion (January 1, 2014-June 30, 2017) periods. These measures were compared between expansion versus nonexpansion states during the postexpansion period. The cohort included 58 804 patients hospitalized across 391 sites. In states that expanded Medicaid, uninsured HF hospitalizations declined from 7.9% to 4.4%, and Medicaid HF hospitalizations increased from 18.3% to 34.6%. Defect-free HF care was increasing during the preexpansion period (adjusted odds ratio/quarter, 1.06; 95% confidence interval, 1.03-1.08) but did not change after expansion (adjusted odds ratio, 0.99; 95% confidence interval, 0.97-1.02). Patterns were similar for other quality measures. There were no quality measures for which the rate of improvement sped up after expansion. In-hospital mortality rates remained similar during the preexpansion (adjusted odds ratio, 0.99; 95% confidence interval, 0.96-1.02) and postexpansion periods (adjusted odds ratio, 1.00; 95% confidence interval, 0.97-1.03). Among nonexpansion states, uninsured HF hospitalizations increased (11.6% to 16.7%) as did Medicaid HF hospitalizations (17.9% to 26.6%), and no quarterly improvement was observed for most quality measures in the post compared with preexpansion period. During the postexpansion period, defect-free care and mortality did not differ between expansion and nonexpansion states.

Conclusions

Medicaid expansion was associated with a significant decline in uninsured HF hospitalizations but not improvements in quality of care or in-hospital mortality among sites participating in a national quality improvement initiative. Efforts beyond insurance expansion are needed to improve in-hospital outcomes for low-income patients with HF.

Background

There are limited data on the safety of intravenous recombinant tissue plasminogen activator (rtPA) for treating acute ischemic stroke in patients with gastrointestinal malignancy or recent gastrointestinal bleeding within 21 days of their index stroke.

Aims

To evaluate clinical outcomes in patients treated with rtPA for acute ischemic stroke who had gastrointestinal malignancy or recent gastrointestinal bleeding.

Methods

We identified patients who were treated with rtPA for acute ischemic stroke between 2/2009 and 12/2015 from the Get With The Guidelines-Stroke linked to Medicare claims data. Gastrointestinal malignancy and recent gastrointestinal bleeding were defined as any gastrointestinal malignancy hospitalisation within one year prior to acute ischemic stroke and gastrointestinal bleeding hospitalisation within 21 days prior to acute ischemic stroke, respectively. Outcomes of interest included in-hospital mortality and bleeding complications.

Results

Among 40,396 patients aged 65 years or older treated with rtPA for acute ischemic stroke from 1522 sites (mean age [SD] 81.0 [8.1] years; 41.9% women), 136 (0.3%) had gastrointestinal malignancy (n = 96) or recent gastrointestinal bleeding (n = 43). Patients with gastrointestinal malignancy or bleeding had more severe stroke than those without (median NIHSS [interquartile range]: 14.0 [8.0-19.0] vs. 11.0 [6.0-18.0]). The rates of in-hospital mortality and life-threatening systemic haemorrhage were not significantly different between those with and without gastrointestinal malignancy or bleeding (mortality: 10.3% vs. 9.0%, adjusted odds ratio [aOR] 1.01, 95%CI 0.58-1.75; bleeding: 2.3% vs. 1.2%, aOR 1.72, 95%CI 0.58-5.11).

Conclusions

In this observational cohort, we did not find increased risk of in-hospital mortality and bleeding in rtPA-treated patients with gastrointestinal malignancy or recent gastrointestinal bleeding.

Aims

Post-stroke hypertension is associated with poor short-term outcome, although the results have been conflicting. Our objective was to evaluate the association of blood pressure (BP) and in-hospital outcomes in patients with acute ischaemic stroke.

Methods and results

Patients in the Get With The Guidelines-Stroke registry with acute ischaemic stroke were included. Admission systolic and diastolic BP was used to compute mean arterial pressure (MAP) and pulse pressure (PP). The outcomes of interest were: in-hospital mortality, not discharged home, inability to ambulate independently at discharge and haemorrhagic complications due to thrombolytic therapy. A total of 309 611 patients with an ischaemic stroke were included. There was a J-shaped/U-shaped relationship between systolic BP and outcomes. Both lower and higher systolic BP values, compared with a central reference value, had higher risk of in-hospital death [e.g. adjusted odds ratio (95% confidence interval) (OR[CI]) = 1.16[1.13-1.20] for 120 vs. 150 mmHg and 1.24[1.19-1.30] for 200 vs. 150 mmHg], not discharged home (OR[CI] = 1.11[1.09-1.13] for 120 vs. 150 mmHg and 1.15[1.12-1.18] for 200 vs. 150 mmHg), inability to ambulate independently at discharge (OR[CI] = 1.16[1.13-1.18] for 120 vs. 150 mmHg and 1.09[1.06-1.11] for 200 vs. 150 mmHg). However, risk of haemorrhagic complications of thrombolytic therapy was lower with lower systolic BP (OR[CI] = 0.89[0.83-0.97] for 120 vs. 150 mmHg), while higher with higher systolic BP (OR[CI] = 1.21[1.11-1.32] for 200 vs. 150 mmHg). The results were largely similar for admission diastolic BP, MAP, and PP.

Conclusion

In patients hospitalized with ischaemic stroke, J-shaped, or U-shaped relationships were observed between BP variables and short-term outcomes. However, haemorrhagic complications with thrombolytic therapy were lower with lower BP.

Hypertensive emergency is a clinical entity with potentially serious health implications and high healthcare utilization. There is a lack of nationally representative data on incidence, causes, and predictors of 30-day readmission after hospitalization for hypertensive emergency. We used the 2013 to 2014 Nationwide Readmissions Database to identify index hospitalizations for hypertensive emergency. Primary outcome was all-cause unplanned 30-day readmission. Multivariable hierarchical logistic regression was used to identify independent predictors of readmission. There were 166 531 index hospitalizations for hypertensive emergency representative of 355 627 (SE, 9401) hospitalizations nationwide in 2013 to 2014. Mean age was 66.0 (SE, 0.14) years, and 53.7% were women. The overall incidence of unplanned 30-day readmissions was 17.8%. The most common causes of readmission were heart failure (14.2%), hypertension with complications (10.2%), sepsis (5.9%), acute kidney injury (5.1%), and cerebrovascular accident (5.1%). Noncardiovascular causes accounted for 57.9% of readmissions. We found age <65 years (odds ratio, 1.21; 95% CI, 1.17-1.25; P<0.001), female sex (odds ratio, 1.09; 95% CI, 1.07-1.12; P<0.001), comorbid disease burden, substance use disorders, and socioeconomic risk factors to be significant predictors of readmission. One out of 6 patients hospitalized for hypertensive emergency had an unplanned 30-day readmission. Heart failure, uncontrolled hypertension, and stroke were among the most frequent causes of readmission; however, over half of all readmissions were because of noncardiovascular causes.