Hypertension / Acute HF / Stress Echocardiography / Kidney Disease

Educational Objectives

After hearing and assimilating this program, the listener will be better able to:

1. Increase his/her basic knowledge of important advances in medicine.
2. Identify a broad range of clinical research reported in the medical literature.
3. Synthesize research findings through one-on-one interviews with authors, editorialists, or experts in the field.
4. Integrate new treatments reviewed in the summaries into current practice.
5. Challenge oneself with thoughtful, clinically relevant questions.

Summary

Summary Narrators

Carole Wyand

Tom Linden, MD
Professor of Medical Journalism
University of North Carolina, Chapel Hill

CHLORTHALIDONE vs. HYDROCHLOROTHIAZIDE FOR HYPERTENSION

Which diuretic should be recommended for the first-line treatment of patients with hypertension? To answer that question, researchers used retrospective data from three United States administrative claims databases to compare about 40,000 patients who took chlorthalidone and 700,000 patients who took hydrochlorothiazide. Details appear on the website of JAMA Internal Medicine (https://doi.org/10.1001/jamainternmed.2019.7454).

In analyses that were adjusted for potential confounding factors, the researchers found no differences between the two groups for any cardiac endpoint (namely, myocardial infarction, hospitalization for heart failure, hemorrhagic or ischemic stroke, and a composite measure of these three outcomes plus sudden cardiac-related death). Significant relative differences favored hydrochlorothiazide for a few safety outcomes (like hypokalemia), but the absolute differences were small.

The 2017 guideline from the American College of Cardiology and the American Heart Association expresses a preference for chlorthalidone over hydrochlorothiazide, based on chlorthalidone’s performance in comparisons with nondiuretic drug classes in several large randomized trials (www.jwatch.org/na45488). But chlorthalidone and hydrochlorothiazide have not been directly compared in a large randomized trial. This observational study does not provide compelling evidence to favor either drug, but a large randomized comparison is underway in the U.S. Veterans Affairs health system (Diuretic Comparison Project https://clinicaltrials.gov/ct2/show/NCT02185417).

TAKING ON DIURETIC RESISTANCE IN PATIENTS WITH ACUTE HF

Diuretic resistance creates challenges in managing acute decompensated heart failure. Current guidelines, based only on expert consensus, recommend supplementing loop diuretics with thiazides. In a study in the March 2020 issue of JACC: Heart Failure (https://doi.org/10.1016/j.jchf.2019.09.012), researchers examined three strategies in 60 patients with heart failure and an average age of 62, a quarter of whom had preserved systolic function; the patients were hospitalized with volume overload and diuretic resistance (defined as less than 2 L of total urine output for 12 hours before they were enrolled in the study, despite at least 240 mg/day of a furosemide equivalent). Patients with severe renal dysfunction and hypotension were excluded.

The patients were randomized to 5 mg of oral metolazone twice/day; 500 mg of intravenous chlorothiazide twice/day; or 30 mg/day of oral tolvaptan, which is a vasopressin-2 channel antagonist. All of the patients also got a high-dose, continuous-infusion loop diuretic (580 mg/day or 820 mg/day of a furosemide equivalent depending on pre-enrollment dose), a fluid restriction of 2 L/day, and a sodium restriction of 2 g/day. All three of the regimens were associated with improved urine output, and they were similar in the primary endpoint of weight loss in 48 hours (means: Metolazone, −4.6 kg; chlorothiazide, −5.8 kg; tolvaptan, −4.1 kg). Serum sodium decreased less with tolvaptan than with metolazone.

Escalating diuretic regimens with a high-dose continuous-infusion loop diuretic plus a second agent achieves negative fluid balance in patients hospitalized with heart failure and diuretic resistance. Although sample size limits the power of this study, the three approaches show no meaningful differences. Cost is key: Both tolvaptan and IV chlorothiazide cost approximately US$500 per dose, compared with US$1 for oral metolazone. So a metolazone-first strategy in conjunction with a continuous-infusion loop diuretic makes good sense in this clinical scenario.

This study was industry-sponsored.

PROGNOSTIC IMPLICATIONS OF DISCORDANT ECG AND IMAGING ON STRESS ECHOCARDIOGRAPHY

Stress echocardiogram testing is used to assess multiple endpoints, including exercise electrocardiographic and imaging results. But what does it mean when electrocardiographic and imaging results are discordant? In a study on the website of JAMA Internal Medicine (https://doi.org/10.1001/jamainternmed.2019.6958), researchers at a single center evaluated the prognostic implications of discordant results in 15,000 consecutive patients without known coronary artery disease who underwent stress echocardiography.

Most of the patients (85.5%) had negative results on both electrocardiography and imaging, but 9% had positive electrocardiograms with negative imaging, and 6% had positive imaging (regardless of the electrocardiographic results). After a median follow-up of 7 years, a composite endpoint of death, myocardial infarction, hospitalization for unstable angina, and coronary revascularization was seen in 9% of those with negative results; 15% of those with positive electrocardiograms, but with negative imaging; and 40% of those with positive imaging. The rates of additional downstream testing (within a year after stress echocardiography) also increased progressively across the three categories. Among the patients with positive imaging, electrocardiographic results further stratified the risk (meaning that the primary endpoint was seen in a quarter of those with negative electrocardiograms and in half of those with positive electrocardiograms).

This large, albeit single-center, study confirms what experienced clinicians and smaller studies have suggested — that much of the prognostic value of stress echocardiography seems to be contained in the imaging result, and those with positive imaging tests can be categorized as a high-risk group, but those with positive electrocardiographic results and negative imaging have a modest excess risk for adverse events compared with the patients with concordant negative results. Although the best way to treat patients with positive electrocardiographic and negative imaging results is not entirely clear, this study’s findings suggest that these patients undergo more downstream testing, presumably to clarify their discordant results.

GUIDELINE WATCH: USE OF IV CONTRAST IN PATIENTS WITH RENAL DISEASE

Recent observational studies with sophisticated statistical adjustment suggest that the alleged risks for acute kidney injury caused by intravenous (IV) iodinated contrast have been overstated. A consensus statement from the American College of Radiology and the National Kidney Foundation incorporates the newer data to provide updated guidance for clinicians. Details appear in the March 2020 issue of Radiology (https://doi.org/10.1148/radiol.2019192094).

• The researchers distinguish between contrast-associated acute kidney injury and contrast-induced acute kidney injury. In many patients who develop acute kidney injury after receiving IV contrast, other coexisting factors (like nephrotoxic medications and fluctuating volume status) make it difficult to prove that contrast media caused the acute kidney injury. Contrast-associated acute kidney injury is the umbrella term describing a temporal association between IV contrast and acute kidney injury, and contrast-induced acute kidney injury is the subset in which cause and effect is likely.
• The risk for contrast-induced acute kidney injury is negligible in patients with estimated glomerular filtration rates (GFRs) of 30 mL/minute/1.73 m2 or higher. In patients with lower GFRs, the estimated incidence of contrast-induced acute kidney injury ranged from 0% to 17%, depending on the study.
• Radiologists and referring clinicians should discuss the potential benefits and risks of IV contrast for patients with a GFR lower than 30 mL/minute/1.73 m2.
• In patients with a GFR lower than 30 mL/minute/1.73 m2, volume expansion with normal saline is recommended, beginning shortly before the radiologic procedure (unless the patient has heart failure), and nephrotoxic medications should be withheld (if clinically feasible) before giving IV contrast.

The most eye-catching item here is the wide-ranging estimate of the risk for contrast-induced nephropathy (between 0% and 17%) when glomerular filtration rate is lower than 30 mL/minute/1.73 m2. This range reflects varied results from observational studies, some of which compared propensity-matched exposed cases and controls to minimize confounding, but these studies included relatively few patients with GFRs lower than 30 mL/minute/1.73 m2. In any case, this consensus statement sensibly concludes that, if imaging with IV contrast (for example, computed tomography) will likely yield critical information for patient management (and if alternative imaging modalities would be inadequate), the imaging study should be performed, regardless of renal function.

HYDRATION BEFORE CONTRAST-ENHANCED CT IN PATIENTS WITH CHRONIC KIDNEY DISEASE?

The established practice of prehydration for patients with chronic kidney disease who are undergoing contrast-enhanced computed tomography (CT) is not fully supported by randomized trial evidence. In a study on the website of JAMA Internal Medicine (https://doi.org/10.1001/jamainternmed.2019.7428), researchers in the Netherlands randomized 520 patients with a median age of 74 and with stage 3 chronic kidney disease either to no prehydration or to prehydration with 250 mL of 1.4% sodium bicarbonate infused during 1 hour before outpatient contrast-enhanced CT. Roughly half of each group had baseline estimated glomerular filtration rates (GFRs) of 30 mL/minute/1.73 m2 to 44 mL/minute/1.73 m2, and half had estimated GFRs of 45 mL/minute/1.73 m2 to 59 mL/minute/1.73 m2.

The average relative increases in serum creatinine levels were similar in the two groups at 2 days to 5 days following their procedures (≈3.0%). The development of postcontrast acute kidney injury (defined as a serum creatinine increase of 25% or greater) was seen in similar percentages of the two groups (roughly 2%).

These results reassure clinicians that prehydration with sodium bicarbonate is not needed to prevent additional renal injury in patients with stage 3 chronic kidney disease. It’s important to know that a recently published guideline in the United States advises against prehydration for most patients with estimated glomerular filtration rates of 30 mL/minute/1.73 m2 or higher (www.jwatch.org/na51000); for patients with lower estimated GFRs, volume expansion with normal saline (but not sodium bicarbonate) is recommended, unless a patient has a contraindication, like heart failure.

Readings

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose.

Acknowledgements

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

JW310602

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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