Troponin, vitamin D, and more

Research summaries from ACP Hospitalist Weekly.

Troponin may not safely rule out inducible myocardial ischemia in symptomatic stable CAD

Very low levels of high-sensitivity cardiac troponin may not be accurate for ruling out inducible myocardial ischemia in certain patients, according to a recent study.

Researchers in Switzerland performed a prospective diagnostic cohort study at a university hospital to determine whether using very low levels of high-sensitivity cardiac troponin I (hs-cTnI) could safely and effectively exclude inducible myocardial ischemia in symptomatic patients with stable coronary artery disease (CAD). Consecutive patients with CAD who were referred with symptoms that could be due to inducible myocardial ischemia were eligible for the study. Expert interpretation of myocardial perfusion imaging with single-photon emission computed tomography was used to determine the presence of inducible myocardial ischemia, along with coronary angiography and fractional flow research measurements when these methods were available.

A cutoff of 2.5 ng/L was used for hs-cTnI, which was previously derived in mostly asymptomatic patients. Predefined target performance criteria for inducible myocardial ischemia exclusion were at least 90% negative predictive value and at least 90% sensitivity. Sensitivity analyses were done using three assays: an hs-cTnI assay with a limit of detection of 1.1 to 1.9 ng/L, an hs-cTnI assay with higher analytic sensitivity, and a high-sensitivity cardiac troponin T (hs-cTnT) assay. Study results were published Jan. 7 by Annals of Internal Medicine and appeared in the Feb. 4 issue.

A total of 1,896 patients with CAD and clinical suspicion of inducible myocardial ischemia were included in the study. The median age was 69 years, and 19% were women. Overall, 865 (46%) were determined to have inducible myocardial ischemia and 1,031 (54%) were not. Pretest probability of inducible myocardial ischemia before stress testing, as predicted by the treating physician based on all available clinical information, ranged from 1% to 100% (median, 50%; interquartile range, 30% to 70%).

The cutoff of 2.5 ng/mL for hs-cTnI to exclude inducible myocardial ischemia yielded a negative predictive value of 70% (95% CI, 64% to 75%) and a sensitivity of 90% (95% CI, 88% to 92%). No hs-cTnI cutoff achieved both of the predefined target criteria, and no cutoff achieved the target performance with the alternative assays. The negative predictive value was 66% (95% CI, 59% to 72%) for an hs-cTnT concentration below 5 ng/L and 68% (95% CI, 62% to 74%) for an hs-cTnI concentration below 2 ng/L.

The authors noted that the study data were from a single institution, that some patients may have been misclassified, and that female patients and patients of African and Asian descent were underrepresented. They concluded, however, that very low hs-cTn concentrations cannot safely exclude inducible myocardial ischemia in symptomatic patients with CAD, writing that their findings “corroborate and extend previous work indicating that the prognostic potential of hs-cTnI or hs-cTnT concentrations is much higher for cardiovascular death than for nonfatal ischemic events, such as [acute MI] and coronary revascularization.”

An accompanying editorial questioned whether coronary artery stenoses need to be diagnosed in stable CAD, since revascularization won't benefit such patients but may cause harm. Although the current study concludes that hs-cTn concentrations cannot safely exclude inducible myocardial ischemia and therefore obstructive CAD, it may not need to be excluded at all, the editorialists said. “Rather, should the focus of testing in patients with stable CAD be on safely ruling out significant pathology, such as left main artery disease (revascularization likely to have net benefit), while preventing unnecessary invasive tests and interventions (likely to have net harm) in most patients?” the editorialists wrote. “Whether hs-cTn has a role in such a triage process remains unclear.”

High-dose vitamin D didn't improve mortality in ICU patients with baseline deficiency

Vitamin D supplementation did not improve outcomes in critically ill patients with vitamin D deficiency, a recent study found.

The phase 3 trial include 1,078 critically ill patients who were found to be vitamin D deficient at baseline (25-hydroxyvitamin D level <20 ng/mL). Within 12 hours of ICU admission, they were randomized to either a single enteral dose of vitamin D3, 540,000 IU, or a matched placebo. The primary analysis included 538 patients in the vitamin D group and 540 in the placebo group. Results were published by the New England Journal of Medicine on Dec. 11, 2019.

The trial, which was meant to enroll 3,000 patients, was stopped early due to lack of benefit from the intervention on the primary outcome of 90-day mortality: 23.5% in the vitamin D group versus 20.6% in the placebo group (difference, 2.9 percentage points; 95% CI, −2.1 to 7.9 percentage points; P=0.26). On day 3, the mean 25-hydroxyvitamin D level was 46.9±23.2 ng/mL in the vitamin D group and 11.4±5.6 ng/mL in the placebo group (difference, 35.5 ng/mL; 95% CI, 31.5 to 39.6 ng/mL). There were no significant differences between groups on secondary clinical, physiological, or safety end points or in the subgroups of patients with more severe vitamin D deficiency or with higher mortality risk.

The study showed that the single vitamin D dose rapidly corrected deficiencies but did not provide any improvement in mortality or other clinically important endpoints, the authors said. They noted that the study differed in several ways from the phase 2 trial that led to it, including enrolling patients sooner after ICU admission, enrolling more typical medical patients rather than surgical or neurological patients, only providing one dose of vitamin D, and having a more ethnically diverse patient population.

“The results of the present trial do not support early testing for or treatment of vitamin D deficiency in critically ill patients,” the authors said. They noted that ongoing studies are investigating longer-term outcomes of vitamin D supplementation and the effects on patients with severe vitamin D deficiencies or other subgroups that may be more likely to benefit.

No significant effect seen from routine oxygen therapy in normoxic patients with MI

Patients with confirmed myocardial infarction (MI) and normal oxygen saturation do not appear to benefit from routine oxygen therapy, a recent study found.

The DETO2X-AMI (DETermination of the role Oxygen in suspected Acute Myocardial Infarction) trial, which randomly assigned 6,629 patients in Sweden with normal oxygen saturation and suspected MI to receive oxygen, 6 L/min, for six to 12 hours, or ambient air, found no evidence that oxygen was associated with reduced mortality over one year. European guidelines now recommend oxygen treatment only in hypoxemic patients with suspected MI, but controversy persists. The DETO2X-AMI researchers therefore performed a subgroup analysis of their trial in which patients with confirmed MI were divided into low-normal (90% to 94%) and high-normal (95% to 100%) cohorts of baseline oxygen saturation. A composite end point of all-cause death, rehospitalization with MI, or heart failure was evaluated at one year, with all follow-up time between one and four years included post hoc. The study results were published by JACC: Cardiovascular Interventions on Dec. 11, 2019, and appeared in the February issue.

Image by Getty Images
Image by Getty Images

The subgroup analysis included 5,010 patients, 836 (17%) in the low-normal cohort and 4,174 (83%) in the high-normal cohort. Of these, 2,485 were assigned to oxygen and 2,525 were assigned to ambient air. Hypoxemia developed in 57 patients assigned to oxygen (2%) versus 231 patients assigned to ambient air (9%). The composite end point occurred more frequently in the low-normal cohort than in the high-normal cohort (17.3% vs. 9.5%; P<0.001) and was most common in patients who developed hypoxemia (23.6%). Oxygen therapy did not appear to be associated with improved outcomes versus ambient air, regardless of patients' oxygen saturation. Death from any cause occurred in 8.3% of patients in the oxygen cohort and 8.9% of the ambient air cohort.

The authors noted that they could not measure how much oxygen patients actually received and that statistical power to detect differences in outcomes was low, among other limitations. They concluded, however, that no clinically relevant benefit was seen with routine oxygen therapy in MI patients with normal oxygen saturation at baseline and that their results are consistent with current guidelines. “Oxygen saturation at baseline in the low-normal range was identified as an important independent marker of poor prognosis that was not affected by oxygen treatment,” the authors wrote.

An accompanying editorial agreed that the study's results do not support changes to guidelines for oxygen therapy in MI but noted that the “true physiological effect of the intervention” was uncertain, since the oxygen was delivered in a real-world clinical setting and patients may not have received the full 6 L/min.

“Perhaps we should once again think about oxygen therapy in terms of its indication, contraindications, dose, route of administration, and monitoring for outcome and toxicity—just as with any other pharmaceutical intervention,” the editorialists wrote. “An extended benefit of re-adopting these longstanding, simple principles of oxygen administration is that the same principles of oxygen treatment of MI are applicable to other potentially ischemic conditions such as transient ischemic attacks, stroke, fetal distress, neonatal resuscitation, and perioperative management.”

Elevated troponin levels associated with increased mortality in all age groups

Patients of any age with elevated troponin levels have increased risk of mortality, particularly in the first weeks after the positive test result, a recent study found.

The retrospective cohort study included 257,948 consecutive patients from five cardiovascular centers in the United Kingdom who underwent troponin testing for any clinical reason in 2010 to 2017. The study assessed the association between the highest troponin level measured during a patient's hospital stay and three-year mortality risk. The troponin levels were standardized across centers as a multiple of each laboratory's 99th centile of the upper limit of normal. Results were published by The BMJ on Nov. 21, 2019.

During a median follow-up of 1,198 days (interquartile range, 514 to 1,866 days), 21.7% of the patients died. A troponin level above the upper limit of normal was associated with a threefold increase in mortality risk during follow-up (hazard ratio [HR], 3.2; 95% CI, 3.1 to 3.2). The association was stronger in younger patients (HR in those 18 to 29 years of age, 10.6 [95% CI, 8.5 to 13.3]; HR in those older than age 90 years, 1.5 [95% CI, 1.4 to 1.6]). Across all age groups, a high troponin level was associated with about 15 percentage points higher risk of mortality, with the risk being heavily concentrated in the first few weeks after testing.

In patients who weren't diagnosed with acute coronary syndrome (n=120,049), increasing troponin level and mortality risk had a direct relationship. However, for patients who did have acute coronary syndrome, there was an inverted U-shaped pattern, so that patients with a troponin level greater than 70 times the upper limit of normal actually had lower mortality. After multivariable adjustment, this pattern persisted only in the patients who were managed invasively. In those treated with noninvasive therapy, troponin level and mortality were directly correlated.

The authors noted that this inverted U-shaped pattern was unexpected. They suggested it could be attributed to changing case-mix at higher troponin levels, plus they noted a high proportion of these patients underwent an invasive procedure. The results of the study can help inform clinicians who receive troponin measurement results, the authors said, although they noted that there is no consensus on how best to manage patients with elevated troponin levels but not acute coronary syndrome.

“Although even weakly raised troponin levels had marked prognostic significance, clinical decisions should depend on the underlying disease and not simply on the degree of increase in troponin,” they wrote. The finding that mortality risk was particularly increased in the few weeks after testing does suggest that “a conservative wait and see approach may not be appropriate,” the authors said.

Limitations of the study include that it was retrospective and not necessarily able to account for all confounding factors. The study also didn't have any information about why patients' troponin levels were measured and the authors were not able to accurately distinguish acute from chronic myocardial injury.

Medications that can exacerbate heart failure often continued despite heart failure hospitalization

Medications that are known to exacerbate heart failure were often still prescribed to patients after they were hospitalized for heart failure, according to a recent study of Medicare beneficiaries.

The study used the Reasons for Geographic and Racial Difference in Stroke study to identify 558 Medicare beneficiaries ages 65 years or older who were hospitalized for heart failure between 2003 and 2014. Researchers looked at the patients' receipt of prescriptions listed in the 2016 American Heart Association (AHA) Scientific Statement on medications that can precipitate or induce heart failure. Results of the study were published by JACC: Heart Failure on Nov. 4, 2019, and appeared in the January issue.

At admission, 41% of patients were on heart failure-exacerbating medications, and at discharge, 36% were. The most common exacerbating medications at admission were albuterol, metformin, NSAIDs, and diltiazem. At discharge, they were albuterol, diltiazem, and metformin. Between admission and discharge, 18% of patients had a decrease in their number of heart failure-exacerbating medications, while 19% stayed on the same number and 12% had an increase. Multivariable logistic regression analysis found that diabetes (odds ratio [OR], 1.8; 95% CI, 1.18 to 2.75) and small hospital size (OR, 1.93; 95% CI, 1.18 to 3.16) were associated with use of exacerbating medications.

The appropriate use of these medications is complicated, the study authors acknowledged. They offered the example of albuterol, which was prescribed in one out of four discharges. It is among the more than 70 medications on the AHA's list, but it is also first-line therapy for chronic obstructive pulmonary disease and asthma. “Our findings highlight the limitations of disease-specific clinical practice guidelines, which cannot account for competing risks and competing priorities. They also underscore importance of incorporating clinical judgment when applying guidelines and scientific statements to patient care, whether they promote prescribing or deprescribing,” the authors wrote.

Many diabetes medications are also on the list, explaining why diabetes was an associated factor. “Simply stopping these agents to treat and subsequently prevent a future [heart failure] exacerbation may not be the optimal strategy, as this can worsen glucose control and thus worsen outcomes. However, switching to other less-offending agents, when feasible, might be a reasonable approach to adopt,” the authors wrote. They called for the development of additional strategies to improve the safety of prescribing for this vulnerable population.

Limitations of the study include that it only looked at standing prescriptions, not medications that were given as needed, and that some of the medications on the list may be harmful only in certain circumstances or have more recent data to support their use in heart failure patients.

STEMI outcomes similar whether patients present on or off hours, French study finds

Patients presenting to one hospital with ST-segment elevation myocardial infarction (STEMI) received similar care and had similar outcomes at one year regardless of time of admission, according to a recent study.

Researchers in France looked at the characteristics and clinical outcomes of 2,167 consecutive patients with STEMI who were admitted to a tertiary care center for percutaneous coronary intervention (PCI), with the goal of determining the effect of admission time on outcomes. Admission was considered the arrival time at the catheterization laboratory. On-hours admission was defined as admission from Monday to Friday between 8 a.m. and 6 p.m., and off-hours admission was defined as admission during the night shift, on a weekend, or on a nonworking holiday. The primary outcomes were in-hospital and one-year all-cause mortality, and secondary outcomes were key time delays and therapeutic management. The study results were published Oct. 30, 2019, by JACC: Cardiovascular Interventions and appeared in the November 2019 issue.

Overall, 1,048 patients (48.3%) had on-hours admissions and 1,119 (51.7%) had off-hours admissions. Rates of cardiac arrest, cardiogenic shock, and other characteristics were similar between groups. One-year follow-up data were available for 95.3% of patients. No between-group difference was seen in median time from symptoms to first medical contact (120 min for on-hours admission vs. 126 min for off-hours admission; P=0.25) or in median time from first medical contact to sheath insertion (90 min vs. 93 min, respectively; P=0.58). Rate of radial access for catheterization (85.6% vs. 87.5%, respectively; P=0.27) did not differ between groups, and no difference was seen for in-hospital (8.1% vs. 7.0%; P=0.49) and one-year mortality rates (11.0% vs. 11.1%; P=0.89).

The researchers noted that their study was done at a single, high-volume center in an urban STEMI network using radial primary PCI and that they used sheath insertion time rather than door-to-balloon time as an outcome measure. However, they concluded that time of admission was not associated with risk for death at one year in STEMI patients. “Our analysis demonstrates that a well-organized urban STEMI network allows [facilities] to bridge the gap between on-hours and off-hours management and provide the same quality of care whatever time of admission,” the authors wrote.

The author of an accompanying editorial called the results of the study “aspirational,” noting that France has a nationwide prehospital emergency response system with a mobile ICU that provides intensive care at first medical contact and offers rapid transfer to a PCI-capable facility. “We should all be inspired by this report to continue to pursue more efficient and effective pre-hospital and in-hospital STEMI care,” the editorialist wrote. “Access to [emergency medical services] and primary PCI services, and time-to-treatment, remain the most modifiable variables in the continuing effort to further decrease morbidity and mortality from STEMI.”

Nicotine replacement during surgical hospitalization not associated with adverse outcomes

Receiving nicotine replacement therapy (NRT) while hospitalized for surgery was not associated with adverse postoperative outcomes, a recent study found.

Image by Getty Images
Image by Getty Images

The retrospective study used data from 552 hospitals to follow 147,506 patients who smoked and underwent a major surgical procedure (with expected stay of two days or more) in 2015 or 2016. Within two days of admission, 17.4% of the patients received NRT. Their characteristics and outcomes in the 30 days following surgery were compared to patients who didn't receive NRT. Results were published by CHEST on Nov. 29, 2019, and appeared in the May issue.

Patients treated with NRT were younger, less likely to be black or Hispanic, and more likely to have Medicaid coverage than patients who didn't get NRT. Diagnoses of alcohol or substance use disorder and chronic obstructive pulmonary disease were also associated with receipt of NRT. In a propensity-matched analysis, NRT use was not associated with any change in in-hospital complications (odds ratio [OR], 0.99; 95% CI, 0.93 to 1.05), mortality (OR, 0.84; 95% CI, 0.68 to 1.04), all-cause 30-day readmissions (OR, 1.02; 95% CI, 0.97 to 1.07), or 30-day readmissions for wound complications (OR, 0.96; 95% CI, 0.86 to 1.07).

“These results, in a ‘real-world,’ nationally representative sample, using rigorous analytical methods are significant because they reduce the uncertainty around the safety of NRT use in the immediate postoperative period, suggesting that tobacco treatment does not raise the risk of perioperative complications,” the authors said. They noted that the study found fairly low rates of NRT use among surgical patients, as well as variation both by hospital and by procedure.

Although the authors believe this to be the first large observational study of NRT in surgical patients, the results are consistent with previous observational studies and randomized trials in cardiac patients and the general population, they said. Limitations include the possibility of unmeasured confounding and that they weren't able to differentiate between continuation of outpatient NRT and new inpatient prescription or to tell if NRT was continued at discharge.

Continuing smoking cessation services after hospitalization is necessary in order to increase rates of long-term abstinence, the study authors noted. “It is hypothesized that initiation of NRT during a hospitalization may serve as a bridge for lifelong cessation,” they wrote. “Given that hospitalization is a teachable moment with high patient motivation to quit smoking, there appears to be a large opportunity to improve the care of hospitalized patients who undergo surgery and policies should be developed and implemented to support the use of NRT in surgical patients.”

Staff, vets describe transitions from non-VA hospitals to VA primary care as inefficient

Clinicians at Veterans Administration (VA) and non-VA hospitals, as well as veterans, described the current transitional care process as inefficient, noting difficulties with prescriptions, medical records, and follow-up appointments in a recent qualitative study.

Researchers conducted semi-structured interviews with clinicians, staff, and patients to assess the barriers and facilitators to providing high-quality continuum of care for veterans transitioning from non-VA hospitals to the VA primary care setting. A total of 70 participants were from one urban VA medical center and two non-VA hospitals. Fifty-two clinicians and staff (23 VA and 29 non-VA) involved in patient transition and 18 veterans recently discharged from non-VA hospitals were included in the study. Results were published online on Oct. 23, 2019, by the Journal of Hospital Medicine and appeared in the March issue.

Overall, researchers identified no standardized process for transitioning veterans across health care delivery systems. Participants consistently discussed gaps in four major processes: 1) identifying patients as veterans and notifying VA primary care of discharge, 2) transferring non-VA hospital medical records to VA primary care, 3) obtaining follow-up care appointments with VA primary care, and 4) writing VA formulary medications for veterans that they could fill at VA pharmacies.

However, several participants provided examples of seamless transitional care communication. VA staff and veterans said the VA increased the availability of urgent care appointments, allowing for timelier postacute care follow-up appointments. While non-VA hospital clinicians also noted the available of additional appointment slots, they said they did not learn about them directly from the VA; they learned of them through residents caring for patients at both VA and non-VA hospitals. Participants suggested that implementing a care coordinator with a clinical background may improve the current process.

The study authors noted limitations, such as the fact that the participants' perspectives may not represent all hospital clinicians' and veterans' experiences with transitions of care. They added that the study was conducted in one state, so findings may not be applicable to other settings. “To avoid frustration and inefficiencies, the increased emphasis of providing non-VA care for veterans should consider the challenges experienced in transitional care and the opportunities for increased coordination of care,” the authors concluded.