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Don't Miss a Beat

 who forego COVID-19 vaccinations could be placing themselves into a position where their risk of mortality is 3 times greater than that of their vaccinated counterparts, according to new research from Mount Sinai Health System.

An analysis of electronic medical record data from more than 7000 patients with heart failure across the health system, results of the study, which used inverse probability treatment weight models to adjust for potential confounding, suggested patients who were vaccinated had a 64% reduction in risk of mortality compared to their unvaccinated counterparts, with even further reduction observed among those who received a booster.

“Until now, it has been difficult to explain to these patients how the cardiovascular benefits of vaccination substantially outweigh the risks of complications to them, because we didn’t have concrete evidence to show the substantial risks of being unvaccinated, as few studies have focused on this specific high-risk population and COVID-19 vaccinations,” said senior investigator Anurhada Lala, MD, director of Heart Failure Research and an associate professor of medicine at the Icahn School of Medicine at Mount Sinai, 

. “Having specific data showing patients with heart failure who don’t have their full vaccine series are at a much higher risk of death, intensive care unit (ICU) admission, and general hospitalization—even after accounting for factors that might be related to an individual’s decision to become vaccinated—is helpful.”

With previous reports evidencing a link between increased risk of adverse outcomes with OCIVD-19 among patients with heart failure, Lala and a team of colleagues from the Icahn School of Medicine at Mount Sinai launched the current study with the intent of assessing the impact of COVID-19 vaccine status on clinical outcomes in patients with heart failure. To do so, the investigators designed their study as a retrospective cohort study on the association of VCOVID-19 vaccinations status with hospitalizations, ICU admission, and mortality after adjustment for covariates using data from the Mount Sinai Health System electronic health record database.

From the EHR database, investigators obtained related to a cohort of 7094 heart failure patients who underwent visits from January 1, 2021-January 24, 2022. Of these, 9.1% (n=645) were partially vaccinated, 31.0% (n=2200) were fully vaccinated, 14.8% (n=1053) were vaccine-boosted, and 45.1% (n=3196) were unvaccinated. The overall cohort had a mean age of 73.3±14.5 years, 48% were women, and 63.3% had Medicare insurance. Investigators noted 77.9% had another form of cardiovascular disease, 58.3% had hypertension, and 32.0% had type 2 diabetes. Compared to their unvaccinated and partially vaccinated cohorts, those who were fully vaccinated or vaccine-boosted were older, more likely to be of White race, have Medicare insurance, and have higher rates of multiple comorbidities, including obesity, hypertension, pulmonary disease, and diabetes.

Of the 7094 patients identified for inclusion, 904 died during a mean follow-up time of 276.5±104.9 days. Of those who died during the follow-up period, 73.4% wee unvaccinated or only partially vaccinated. In adjusted analyses, those in the vaccine-boosted cohort had the lowest mortality risk (HR, 0.33 [95% CI, 0.23-0.48]) compared to unvaccinated individuals, followed by full vaccinated patients (HR, 0.36 [95% CI, 0.30-0.43]) (

 <.001). Investigators pointed out there was no significant difference in mortality risk observed among partially vaccinated patients compared to unvaccinated patients (HR, 0.87 [95% CI, 0.68-1.12]; 

=.28). Further analysis indicated fully vaccinated or boosted patients were significantly less likely to be admitted to the hospital (IRR, 0.68 [95% CI, 0.65-0.71]; 

 <.001) or admitted to the ICU (IRR, 0.63 [95% CI, 0.58-0.68]) than their unvaccinated or partially vaccinated counterparts.

“The findings further emphasize that heart failure patients need to take vaccines seriously, since they have worse outcomes if infected with COVID-19, and stresses the importance of receiving the full COVID-19 vaccination dosage, especially since our previous work shows those with heart failure are 2.5 times more likely to die from the virus,” Lala added. “I have used these results to help educate reluctant patients and, in many cases, this has been effective in encouraging them and getting them to follow through with full vaccination. The hope is that cardiologists will use these results as a tool to help their patients and improve their chances of survival.”

Association of Reduced Hospitalizations and Mortality Among COVID-19 Vaccinated Patients with Heart Failure

Articles

A retrospective cohort study of patients from the Mount Sinai Health System EHR suggests patients with heart failure who received a COVID-19 vaccination saw their risk of mortality decreased by more than 60% compared to unvaccinated individuals. 

Forgoing Vaccination Could Increase Mortality Risk in Heart Failure Patients

This article was originally published on 

New research presented at the Associated Professional Sleep Societies (SLEEP) 2022 Annual Meeting suggests obstructive sleep apnea (OSA) could predict an increased risk of future MACE. 

Led by a team of investigators from Brazil and the US, results of the study provide evidence detailing a biological link between excessively sleepy patients and greater risk of cardiovascular disease and events.

Investigators, led by Érique José Farias Peixoto de Miranda, PhD, of the division of clinical trials at the Institute of Butantan in Sao Paulo, analyzed the role of OSA and associated clinical features on coronary artery calcium (CAC) prevalence, incidence and progression to disease in a cohort of participants from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) from 2008 – 2013.

“Recent evidence suggests that symptomatic OSA patients are susceptible to cardiovascular events,” they wrote. “The development of atherosclerosis is a plausible mechanism but the impact of OSA on atherosclerosis is unclear.”

ELSA-Brasil investigators had conducted a series of sleep analyses including patient questionnaires, actigraphy and home sleep studies during the trial. CAC scores were measured by a 64-slice multi-detector computed tomography, with prevalent subclinical atherosclerosis defined as CAC >0 at baseline.

Investigators additionally defined incident atherosclerosis as baseline CAC score of 0 followed by >0 at the patient’s 5-year follow-up visit. CAC progression was defined by baseline score of 0 followed by an increase in scores at follow-up.

OSA was defined by apnea-hypopnea index (AHI) scores of ≥15 events per hour. Del Miranda and colleagues assessed the link between patient OSA and subclinical atherosclerosis prevalence, incidence, and progression via logistic regression. They adjusted each outcome by relevant cardiovascular risk factors. Analyses were additionally stratified based on observed excessive daytime sleepiness (EDS).

The final analysis included 1956 patients with available baseline CAC scores. Mean age was 49 years old; a majority of patients women (57.9%) and 28.2% were diagnosed with OSA.

The team observed a 12 percentage-point increased prevalence of subclinical atherosclerosis in patients with OSA (31.3%) versus those without (19.0%; 

 <.001). In a longitudinal analysis involving 1247 patients followed up with for a mean 5.1 years, the investigators observed a significant association between OSA and incident subclinical atherosclerosis among patients who reported EDS (adjusted odds ratio [OR], 1.97; 95% CI, 1.09 – 3.55; 

Additionally, the team’s analysis of CAC progression among 319 patients showed that OSA was associated with an 8% increased risk of atherosclerosis progression (1.08; 95% CI, 0.03 – 2.14; 

 = .043) while OSA and EDS were associated with a 66% increased risk (1.66; 95% CI, 0.23 – 3.04; 

“OSA, particularly with EDS, predicts the incidence and progression of subclinical atherosclerosis, a validated marker of future cardiovascular events,” investigators concluded. “These results provided biological plausibility for the higher cardiovascular risk observed in excessively sleepy patients.”

The study, “Incidence and Progression of Coronary Calcium Scores in Patients with Symptomatic Obstructive Sleep Apnea: the ELSA-Brasil study,” was presented at SLEEP 2022.

In a study presented at SLEEP 2022, investigators provide an overview of the impact of obstructive sleep apnea and daytime sleepiness with increased risk of atherosclerotic cardiovascular disease.

Examining the Role of Sleep Apnea in Cardiovascular Disease Risk

A patient in their early-60’s with no PMH presents to the hospital with 2 months of gradually worsening dyspnea on exertion that has been worse for the past few days. He thinks the trouble breathing may be an allergic reaction to a new skin cream he is using because the timing seems to fit. He denies syncope, palpitations, chest pain, leg swelling, or other complaints.

Vital signs are as follows: Temp 98.8, BP 115/73, HR 112, RR 21, Sat 92%. Exam is otherwise normal with no rash, leg swelling, stridor, or wheezing/rales.

Computer Read: Sinus tachycardia at 109, cannot rule out inferior infarct of indeterminate age

Our latest case report from Brady Pregerson, MD, features a man in his early 60s presenting with months of gradually worsening dyspnea on exertion that has been worse for several days. Check out the EKG and determine the correct diagnosis!

Case Report: DOE

Muthiah Vaduganathan, MD, MPH, is a cardiologist specializing in cardiorenal metabolism at Brigham and Women's Hospital in Boston, MA. Vaduganathan is a member of Practical Cardiology's advisory board and co-host of Don't Miss a Beat, a podcast presented by Inside Cardiology.

Stephen Greene, MD, is an associate professor of medicine at Duke University School of Medicine and cardiologist at the Duke Clinical Research Institute in Durham, NC. Greene is a member of Practical Cardiology's advisory board and co-host of Don't Miss a Beat, a podcast presented by Inside Cardiology.

With estimates suggesting obstructive hypertrophic cardiomyopathy (oHCM) impacts 1-in-500 patients in the US, the advent of safe and efficacious therapies stands to have immediate and substantial impacts on disease management, quality of life for patients, and the societal burden of the most genetic cardiovascular condition. Because of this, news of 

US Food and Drug Administration’s approval of mavacamten (Camzyos) on April 28

 was welcomed by the cardiology community as a historic advance for the field.

A first-in-class allosteric and reversible inhibitor selective for cardiac myosin approved based on the results of the EXPLORER-HCM trial, mavacamten was approved for the treatment of adults with symptomatic NYHA class 2-3 obstructive HCM after their phase 3 data indicated use was with improved exercise capacity, LVOT obstruction, NYHA functional class, and health status patients with oHCM.

, hosts Stephen Greene, MD, of Duke University School of Medicine, and Muthiah Vaduganathan, MD, MPH, of Brigham and Women’s Hospital, are joined by special guest Anjali Owens, MD, of Penn Medicine. An assistant professor of medicine in the Division of Cardiology and medical director of the Center for Inherited Cardiac Disease at the Perelman School of Medicine, Owens is a leading researcher in oHCM with real-world clinical experience treating the disease, Owens takes our hosts on a deep dive into the disease state from her perspective.

All episodes of Don’t Miss a Beat are available in an audio-only format on 

In the latest edition of Don’t Miss a Beat, hosts Stephen Greene, MD, and Muthiah Vaduganathan, MD, MPH, are joined by special guest Anjali Owens, MD. An assistant professor of medicine and medical director of the Center for Inherited Cardiac Disease at the Perelman School of Medicine, Owens takes our hosts on a deep dive into the current state of management for oHCM and the impact of the US FDA's approval of mavacamten.

Don't Miss a Beat: oHCM and Mavacamten, with Anjali Owens, MD

Using data from the SEARCH for Diabetes in Youth study, new research presented at the American Diabetes Association 82nd Scientific Sessions details racial and ethnic disparities in 

arterial stiffness among patients with type 1 diabetes

Presented by Katherine Sauder, PhD, of the University of Colorado, results of the study suggest racial and ethnic disparities in arterial stiffness are a driver of the cardiovascular risk factors among patients with type 1 diabetes.

"Cardiovascular disease is very common in people with diabetes. And when you have youth onset diabetes, those risks start to increase very early in life. It's not in the 50s and 60s and 70s. But it's much earlier in life. So, we found in the SEARCH for Diabetes in Youth study that we do start to see cardiovascular comorbidities in the early 20s,” said Sauder in an interview with 

“So just 8-10 years after a type 1 diabetes diagnosis, this starts to appear. But it doesn't appear in everybody equally, we found that arterial stiffness, which is a measure of cardiac health was actually more prevalent in non-Hispanic black youth and young adults compared to non-Hispanic whites, and also more common in Hispanics compared to non-Hispanic whites.”

The SEARCH for Diabetes in Youth study followed pediatric patients with diabetes from 10 months up to 11 years after diagnosis at 5 clinical sites in the US. In total, the study collected data related to 1162 participants with type 1 diabetes who had data collected at 3 visits that took place approximately 5 years apart and assessed 6 specific domains, including socioeconomic factors, type 1 diabetes characteristics, cardiovascular risk factors, health behaviors, quality of care, and perception of care. Of note, arterial stiffness was assessed via carotid-femoral pulse wave velocity at 20 years of age.

Of the 1162 participants, 254 identified as Hispanic, 208 identified as non-Hispanic Black, 700 identified as non-Hispanic White. For the purpose of analysis, investigators used generalized linear models to estimate differences in pulse wave velocity (PWV) by race and ethnicity, with adjustment for sex, age at measurement, and SEARCH study center. For each risk factor, investigators assessed the longitudinal data as mean, max, slope, and area-under-the-curve (AUC).

Upon analysis, results indicate racial and ethnic disparities in arterial stiffness were partially explained differences in socioeconomic status and cardiovascular risk factors. Specifically, these factors attenuated the disparity in arterial stiffness seen among Hispanic and non-Hispanic White patients by 21% (

 >.005), the disparity observed between non-Hispanic Black and Hispanic patients by 35% (

 >.005), and the disparity observed between non-Hispanic Black and non-Hispanic White patients by 30% (

“It's partly explained by the traditional cardiovascular risk factors, but only about a third of it. So, two-thirds of what is driving these disparities in cardiovascular disease and type 1 diabetes doesn't appear to be our typical biological factors. That means there are other things that are involved. We found that socioeconomic position was also involved, the household income, the kind of insurance, even access to care. When we ask participants about whether they have missed medications in the prior year because of cost and that, specifically, was linked to these disparities in cardiovascular disease,” Sauder added. “So again, it's not just the straight biological, clinical risk factors that we need to be attending to, but the broader picture, the social determinants of health, all of the things about our lives about these kids’ lives that impact their health long term.”

This study, “Exploring Racial and Ethnic Disparities in Arterial Stiffness in Type 1 Diabetes,” was presented at ADA 2022.

Katherine Sauder, PhD, provides perspective on an ADA 2022 study she led examining racial/ethnic disparities in arterial stiffness among youths with type 1 diabetes in the US. 

Exploring Racial/Ethnic Disparities in Arterial Stiffness in Youth with Type 1 Diabetes

Empagliflozin provides a greater magnitude of risk reduction for 

 than other glucose-lowering agents, according to data from the EMPRISE study.

A real-world comparative effectiveness and safety study comparing empagliflozin against DPP-4 inhibitors and GLP-1 receptor agonists found use of empagliflozin was associated with relative risk reductions greater than 50% against DPP-4 inhibitors and greater than 30% compared against GLP-1 receptor agonists for hospitalizations for heart failure among patients with type 2 diabetes.

“With more than 29 million people in the U.S. diagnosed with type 2 diabetes, up to 22% of whom may also have heart failure, it is critical that healthcare professionals caring for this population have treatments that demonstrate cardiovascular effectiveness in routine care,” said co-investigator Elisabetta Patorno, MD, DrPH, of the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, 

A 5-year monitoring program assessing the effectiveness and safety of empagliflozin using the Medicare, Optum Informatics, and IBM MarketScan databases from 2014-2019, the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) study created propensity-matched cohorts from the aforementioned databases and compared the agents for incidence of heart failure hospitalization in primary or discharge positions. The specific primary outcome of interest was incidence of heart failure hospitalization in primary (HHF-Specific) or any discharge positions (HHF-Broad), a composite of myocardial infarction (MI) and stroke, and all-cause mortality, which was only assessed in patients with Medicare claims data. The safety outcomes interest for the trial were incidence of lower-limb amputations, nonvertebral fractures, diabetic ketoacidosis (DKA), acute kidney injury (AKI), renal and bladder cancers.

When comparing empagliflozin against DPP-4 inhibitors, investigators had obtained data related to cohorts of 136,937 new empagliflozin users and 599,537 new DPP-4 inhibitor users before propensity score-matching. After propensity score-matching, investigators were left with a pair of cohorts containing 115,116 individual patients. Investigators noted these individuals were matched based on 140 baseline patient characteristics.

Upon analysis, results indicated use of empagliflozin was associated with a reduced risk of heart failure hospitalizations, with reductions observed for the HHF-Specific outcome, (HR, 0.47 [95% CI, 0.41-0.55]) and the HHF-Broad outcome (HR, 0.67 [95% CI, 0.62-0.72]), and all-cause mortality (HR, 0.56 [95% CI, 0.46-0.68]), but a similar risk of the composite of MI or stroke (HR, 0.92 [95% CI, 0.84-1.02]). When assessing safety, results indicated empagliflozin use was associated with a reduced risk of AKI (HR, 0.73 [95% CI, 0.68-0.78]), an increased risk of DKA (HR, 1.88 [95% CI, 1.51-2.34]), and a similar risk of lower-limb amputations, fractures, and renal and bladder cancers.

When comparing empagliflozin against GLP-1 receptor agonist use, after propensity-score matching, investigators obtained data related to 105,955 new users of empagliflozin and 105,955 new users of GLP-1 receptor agonists. Further matching identified initiators 72,498 pairs of new empagliflozin users and new liraglutide users.

Upon analysis, empagliflozin use was associated with a reduction in risk of had a lower risk of hospitalization for heart failure (HR, 0.62 [95% CI, 0.53-0.71]) and a similar risk of MI (HR, 0.95 [95% CI, 0.85, 1.07]), stroke (HR, 1.09 [95% CI, 0.94-1.27)], and mortality (HR, 0.91 [95% CI, 0.77-1.08]) when compared to GLP-1 receptor agonist use, with these results appearing consistent regardless of cardiovascular disease history. When comparing new empagliflozin users to new liraglutide users, investigators noted the observed trends were similar to comparisons against all GLP-1 receptor agonists.

“These five-year results from EMPRISE, showing empagliflozin was associated with a decreased risk of hospitalization for heart failure and for death, are encouraging data for adults with type 2 diabetes and their care team," Patorno added.

These studies, “Effectiveness and Safety of Empagliflozin in Routine Care: Results from the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) Study,” and “Cardiovascular Effectiveness of Empagliflozin vs. Glucagon-Like Peptide-1 Receptor Agonists or Liraglutide in the EMPRISE Study,” were presented at ADA 2022.

A 5-year monitoring program, data from the EMPRISE study detail the comparative risk reductions provided by empagliflozin against GLP-1 RAs or DPP-4 inhibitors for heart failure hospitalizations. 

Empagliflozin Provides Greater HF Risk Reduction than Other Glucose-Lowering Agents

An elderly male with a past medical history of diabetes and stage 5 chronic kidney disease is brought to the hospital by medics with 2 days of nausea, vomiting and generalized weakness. He denies any chest pain, difficulty breathing, fever, chills, abdominal pain, diarrhea, melena, or other complaints. He has a dialysis fistula but has not yet started dialysis. His home medications include losartan, amlodipine, Lasix, sitagliptin, and Plavix.

He is normotensive however heart rate is in the 20–30s range. His extremities are warm and well perfused with a palpable thrill in the left arm. He is not confused. He has faint crackles in the bases bilaterally with trace lower extremity edema.

Computer Read: Atrial fibrillation at 24, marked LAD, RBBB

Our latest case report from Brady Pregerson, MD, features an elderly male with a past medical history of diabetes and stage 5 CKD presenting with 2 days of nausea, vomiting, and generalized weakness. Check out the EKG and determine the correct diagnosis!

Case Report: Slow AFib?

New research suggests mitral annulus calcification (MAC) could serve as a predictor of increased mortality risk in patients, regardless of whether or not they went on to experience 

A retrospective review of data from more than 24,000 patients evaluated with an EKG by Mayo Clinic clinicians, results of the study indicated MAC was common, present in 23% of patients, and was associated with a doubling in the risk of MVD as well as increased risk of mortality, regardless if patients had MVD or not.

"The association between mitral annulus calcification and mitral valve dysfunction is important to understand because it affects treatment considerations for valve dysfunction," said study investigator Patricia Pellikka, MD, cardiologist at Mayo Clinic, in a 

. "Mitral valve surgery is associated with high risk for patients with mitral annulus calcification, in part because advanced age can be a factor. Severe calcification makes mitral valve procedures more challenging to perform. Our study aimed to assess the characteristics and risk factors of mitral annulus calcification, and the prognostic impact of associations with mitral valve dysfunction."

With support through a grant from Abbott Structural Heart, Pellikka and a team of colleagues from the Mayo Clinic sought to develop a greater understanding of the prevalence and prognostic value of MAC. With this in mind, investigators designed the study as a retrospective review of all adults who underwent transthoracic echocardiography at the Mayo Clinic in Rochester, Minnesota between January 1 and December 31, 2015.

The primary outcome of interest for the study was all-cause mortality. Investigators pointed out patients were censored at the date of mitral valve intervention for both patients with and without MAC in subgroups analyses to assess mortality without mitral valve intervention. For the purpose of analysis, MVD was defined as mitral regurgitation or mitral stenosis of moderate or greeter severity.

During 2015, a total of 24,414 patients underwent evaluation with echocardiography at Mayo Clinic in Rochester, Minnesota. Of these, 23% (n=5502) had MAC. Compared to those without MAC, patients with MAC were older (75±10 vs 60±16 years; 

 <.01) and the prevalence of MAC approved to increase with age. Of the 5502 with MAC, 16% (n=881) experienced MVD. Among those with MAC, those with MVD were more often women (54% vs 44%; 

 <.01) and more frequently frail (52% vs 44%; 

 <.01). Investigators pointed out aortic valve dysfunction, female sex, chest irradiation, renal dysfunction, and coronary artery disease were all associated with mitral stenosis among patients with MAC.

Initial analysis indicated the Kaplan-Meier 1-year survival was 76% among those with MAC and MVD, 87% among those with MAC but no MVD, 86% in those without MAC but with MVD, and 92% in those with no MAC and no MVD. After adjustment for multiple factors, including age, diabetes, renal dysfunction, cancer, chest irradiation, ejection fraction below 50%, aortic stenosis, tricuspid regurgitation, and pulmonary hypertension, MAC was associated with greater risk of mortality (aHR, 1.40 [95% CI, 1.31-1.49]; 

When assessing risk with MVD, results indicated MVD was associated with an additional increase in mortality among patients MAC (aHR, 1.79 [95% CI, 1.58-2.01]; 

 <.001). Investigators pointed out there was no significant interaction observed between MAC and MVD for mortality (

"Mitral annulus calcification has been known to be associated with cardiovascular disease and mortality, but we did not previously appreciate the strength of this relationship even after adjustment for multiple clinical and echocardiographic variables," Pellikka added. "Patients with calcification more commonly had not only mitral valve dysfunction, but also aortic valve disease. For clinicians, suspicion for valve diseases should be increased and evaluations carefully performed for patients with mitral annulus calcification.

Prevalence and Natural History of Mitral Annulus Calcification and Related Valve Dysfunction

A new study from the Mayo Clinic provides insight into the prognostic value of mitral annulus calcification for predicting risk of mortality, regardless of whether or not patients had subsequent mitral valve dysfunction.

Mitral Annulus Calcification Can Predict Increased Risk of Mortality, Mitral Valve Dysfunction 

A new study is adding to the debate surrounding the potential cardiovascular benefits, or lack thereof, associated with fish oil supplements, suggesting consumption of 3 grams per day could provide some relief in those with 

A systematic review and meta-analysis of randomized clinical trials examining the effects of omega-3 fatty acids, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or a combination of both, results depict a J-shaped dose-response curve, with consumption of 3 grams per day, which was determined to be an optimal dose, associated with a mean decrease of in systolic blood pressure of 4.5 mmHg among those with hypertension and about 2 mmHg for those without.

“Our study supports the FDA guidance that EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease by lowering high blood pressure, especially among people already diagnosed with hypertension,” said lead investigator Xinzhi Li, MD, PhD, assistant professor and program director of the School of Pharmacy at Macau University of Science and Technology in Macau, China, 

. “However, while our study may add a layer of credible evidence, it does not meet the threshold to make an authorized health claim for omega-3 fatty acids in compliance with FDA regulations.”

Apart from vitamin D, few topics have garnered as much attention from medical professionals and mainstream outlets for their potential benefits as fish oil. In recent decades, dozens of trials have examined the effects of consumption of various omega-3 fatty acid consumptions, including EPA- and DHA-based agents as well as combination agents. Although some might expect a firm conclusion on the matter with such a wide breadth of clinical trials launched to explore the potential associations, debate still exists surrounding the risks and benefits of omega-3 fatty acids.

With this in mind, Li and a team of colleagues sought to assess the current evidence base detailing use of omega-3 fatty acids for lowering blood pressure and determine the strength and shape of the dose-response relationship. To do so, investigators designed their study as a systematic review and meta-analysis of randomized controlled trials published in the PubMed and Embase databases from inception of the database through May 7, 2021.

Studies of interest for the systematic review and meta-analysis required trials to enroll patients aged 18 years and older and to have examined an association between DHA, EPA, or both and blood pressure. Studies were excluded if they lacked concurrent inactive placebo controls, the intervention duration was less than 4 weeks, if the washout period between treatments in crossover trials was greater than 4 weeks, if patients with hypertension received concurrent antihypertensive agents, and if studies were conducted in pregnant or nursing women, or individuals with preexisting cardiovascular events, renal disease, or secondary hypertension.

From their initial search, investigators identified 3066 relevant articles. After a title and abstract review, a full-text examination was perfumed on 169 articles. Of these, 71 randomized controlled trials were identified for inclusion in their analyses. These studies included a total study population of 4973 individuals.

Investigators noted a random-effects 1-stage cubic spline regression model was used to predict the average dose-response association between daily intake and changes in blood pressure. Investigators also noted that stratified analyses were conducted to determine differences among prespecified subgroups, which included hypertensive, hyperlipidemic, and older populations.

Upon analysis, investigators observed a nonlinear association overall or in most subgroups, which was depicted as a J-shaped dose-response curve. Based on results, the optimal intake of omega-3 fatty acids in both systolic and diastolic blood pressure reductions were between 2 grams per day (systolic: −2.61 [95% CI, −3.57 to −1.65]; diastolic: −1.64 [95% CI, −2.29 to −0.99]) and 3 grams per day (systolic: −2.61 [95% CI, −3.52 to −1.69]; diastolic: −1.80 [95% CI, −2.38 to −1.23]). In subgroup analyses, results pointed to stronger and approximately linear dose-response relationships among patient subgroups defined by hypertension status, presence of hyperlipidemia, and age.

In a related editorial, Marc George, MRCP, PhD, of University College London Hospitals, and Ajay Gupta, MD, PhD, of Queen Mary University of London, highlight the need for further study regarding the potential risk-benefit ratio of EPA- and DHA-based agents as well as combination therapies across a range of cardiovascular conditions.

“Further RCTs and postmarketing studies are required to resolve the remaining questions, particularly one that was raised by the disparity between REDUCE-IT and STRENGTH of EPA monotherapy versus the combination of EPA and DHA. Therefore, omega-3 PUFAs are still not fully ready for prime time, and physicians should keep an open mind on these compounds with acute awareness toward of the mixed evidence base and the potential risks of increased atrial fibrillation and bleeding when prescribing,” George and Gupta wrote.

Omega-3 Polyunsaturated Fatty Acids Intake and Blood Pressure: A Dose-Response Meta-Analysis of Randomized Controlled Trials,

Journal of the American Heart Association.

A systematic review and meta-analysis of more than 70 RCTs details a J-shape dose-response relationship between omega-3 fatty acid consumption and blood pressure, with 2-3 grams per day considered the optimal dose for blood pressure lowering. 

Finding "Sweet Spot" for Omega-3 Fatty Acid Consumption Could Help Lower Blood Pressure

New research from investigators in Canada suggests there was no association between SGLT2 inhibitor use and increase in fracture risk among patients with diabetic kidney disease. 

Conducted by investigators from the Institute for Clinical and Evaluative Sciences (ICES) in Ontario, Canada, the study compared fracture incidence among 38,994 new users of SGLT2 inhibitors and 37,449 new users of DPP-4 inhibitors from linked administrative databases and concluded there was no significant difference in fracture incidence with the agents in weighted analyses assessing risk at 185 and 365 days.

“This study reassures patients and doctors that SGLT2 inhibitors are not associated with an increased risk of fracture in patients with chronic kidney disease,” said Andrea Cowan, MD, of the London Health Sciences Centre in Ontario, Canada, in a 

statement from the American Society of Nephrology

Few agents have received the amount of acclaim and attention as SGLT2 inhibitors in recent years as trials have confirmed their cardiorenal benefits both in and out of diabetes. With these revelations, uptake of these agents has increased markedly in recent years. However, some early trials reported a potential increase in fracture risk with these agents and, while this has been the subject of multiple studies in recent years, some concerns remain around subgroups of patients with diabetes, including those with chronic kidney disease.

With this in mind, investigators hoped to estimate the risk of fracture using SGLT2 inhibitors versus DPP-4 inhibitors in real-world settings. To do so, Cowan and a team of colleagues designed the current study as a population-based cohort study of adults aged 66 years or older with type 2 diabetes and CKD who received a new prescription for SGLT2 inhibitors or DPP-4 inhibitors between July 1, 2015, and September 30, 2019, from a set of 8 linked administrative health databases with data from patients in Ontario, Canada.

The investigators’ initial search yielded an unweighted population of 144,694 patients, with 105,700 new users of DPP-4 inhibitors and 38,994 new users of SGLT2 inhibitors. Using inverse probability of treatment weighting, investigators created cohorts of 37,449 new users of DPP-4 inhibitors and 38,994 new users of SGLT 2 inhibitors for inclusion in their final analyses.

The primary outcome of interest for the analyses was a hospital encounter for a fragility fixture within 180 days of new prescription for either agent. For the purpose of fragility fractures included fractures of the hip, spine, shoulder, upper arm, forearm, wrist, or pelvis. Investigators planned to assess hospitalizations for fragility features at 365 days and site of fracture as secondary outcomes. Additionally, prespecified subgroup analyses were planned to estimate effect by eGFR category.

Among the 76,443 patients included in the study cohort, a total of 342 fractures occurred at 180 days and 689 fractures at 365 days. Upon analysis, results indicated there was no significant difference in fracture risk observed for new users of SGLT2 inhibitors compared with new users of DPP-4 inhibitors at 180 days (HR, 0.95 [95% CI, 0.79-1.13]) and 365 days (HR, 0.88 [95% CI, 0.88-1.00]). In subgroup analyses, results suggested eGFR did not significantly alter the association between SGLT2 inhibitors versus DDP-4 inhibitors and fracture outcomes at 180 (

 for interaction=.53), with no evidence of a higher fracture risk with SGLT2 inhibitors in all eGFR categories.

In an editorial, Mirela Dobre, MD, PhD, a nephrologist in the Division of Nephrology and Hypertension at Case Western Reserve University, detailed the breadth of evidence examining the potential risk of fracture with SGLT2 inhibitors, but noted limitations within the research conducted by Cowan and colleagues and called for further research to determine the real-world risk of fracture with these agents in patient subgroups.

“Deciphering the mechanisms of SGLT2i influence on bone metabolism and fracture risk in individuals with CKD will help design interventions to reduce these devastating consequences. The report by Cowan et al. adds to the growing body of evidence related to the safety of SGLT2is; however, it should encourage continued basic and clinical studies to determine with more certainty their potential risk of fractures, especially in individuals with advanced CKD,” Dobre wrote.

This study, “Fracture Risk of Sodium-Glucose Cotransporter-2 Inhibitors in Chronic Kidney Disease,” was published in the 

Clinical Journal of the American Society of Nephrology.

An analysis of data from more than 75,000 patients with diabetic kidney disease details the risk of fracture among new users of SGLT2 inhibitors compared to new users of DPP-4 inhibitors. 

No Red Flags for Fracture Risk with SGLT2 Inhibitors in Diabetic Kidney Disease

It has long been known that thyroid hormone levels are linked to cardiovascular (CV) regulation and that hyper- and hypo-thyroid states are detrimental to CV health. What is less clearly understood is how the intensity of thyroid hormone therapy affects CV risk and mortality. 

The authors of this study sought to evaluate the association between thyroid replacement intensity and cardiovascular mortality by examining a large pool of data from the Veterans Health Administration database.

Josh Evron, MD, and colleagues looked at 705,307 adults who received thyroid replacement therapy.

 They found that 10.8% of those patients died of cardiovascular causes.

 Thyrotropin and Free T4 levels were gathered for all patients in the study to determine if therapy led to exogenous hypo-, euthyroid, or hyper-thyroid conditions. The authors used regression modeling to produce survival analyses with cardiovascular mortality from myocardial infarction, heart failure, or stroke representing the primary outcomes studied.

The results clearly showed that patients with exogenous hyperthyroidism (thyrotropin levels <0.1 mIU/L) and those with exogenous hypothyroidism (thyrotropin levels >-20mIU/L) had increased risk of cardiovascular mortality when compared to patients who remained euthyroid.

 The association between exogenous hypo- and hyper-thyroid states and mortality increase with higher or lower thyrotropin levels in the hypo- and hyper-thyroid ranges.

This study provides a unique perspective looking at cardiovascular risk based on a very common treatment, thyroid replacement therapy. When prescribing a replacement therapy, the goal of treatment is to achieve a normal level in vivo of whatever hormone you are replacing. This is not as easy as it seems.

Arriving at the appropriate dose takes time and requires frequent measurements of thyrotropin and free thyroxine levels. Even during stable therapy patient factors may change the response, absorption, and metabolism of thyroid hormone. Thus, the intensity of treatment the authors are talking about is a constantly moving target.

The results of this study highlight the importance of regular testing and a willingness among clinicians to put in the work. The authors found that allowing thyroid replacement therapy to fall short or overshoot has real consequences in the form of increased cardiovascular mortality.

This means lives are at stake. This is the essence of a modifiable risk factor. Only, in this case, the modification is not a behavior the patient exhibits but one the clinician is responsible for. The authors state that variability in free T4 levels and thyroid hormone dosage adjustment are inevitable and thus agree with my assertion that regular monitoring and small targeted adjustments are essential parts of not only good thyroid care but also cardiovascular risk mitigation.

These results and conclusions are underscored by the fact that cardiovascular disease is the leading cause of death in the United States. Even though this was an observational study, the results are robust.

An important feature of these results was the linear relationship up and down between the extent of hypo- or hyperthyroid intensity and CV risk. This gives clinicians some room to work while at the same time placing guard rails and warning signs on the limits of acceptability where over and undertreating are concerned.

More work is needed. While the authors have identified an area where we as clinicians can improve, they have also brought up a few new questions. It needs to be determined if there are sex differences in this effect. Further, the degree to which comorbidities were managed was not examined in this study. It is clear however, that tighter observation, monitoring, and intervention are in order with regards to thyroid replacement therapy.

Centers for Disease Control and Prevention. Heart disease. Accessed July 29, 2021. 

https://www.cdc.gov/nchs/fastats/heart-disease.html

Benjamin EJ, Muntner P, Alonso A, et al; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2019 update: a report from the American Heart Association. Circulation. 2019;139(10):e56-e528. doi:10.1161/CIR.0000000000000659

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2792219

Dr. Gregory Weiss breaks down a recent JAMA study that provides estimates of the impact over- and under-treatment with thyroid hormone treatment on cardiovascular disease risk in a cohort of US Veterans.

Too Much or Too Little of a Good Thing: Thyroid Treatment and Cardiovascular Risk

1. Dapagliflozin Meets Primary Endpoint in Phase 3 DELIVER Trial

In a May 5 announcement, AstraZeneca disclosed the phase 3 DELIVER trial had met its primary endpoint, with use of dapagliflozin (Farxiga) associated with a statistically significant and clinically meaningful reduction in the primary composite endpoint.

Announced a little over a month after the release of the ACC/AHA/HFSA 2022 heart failure guidelines, results provide evidence in support of the benefits of SGLT2 inhibitors in HFpEF being a class effect.


2. Study Details in Trends of Cardiovascular Death Among Cancer Patients in US Since 1999

An analysis of data from the CDC’s WONDER database provides an overview of trends in disease-specific cardiovascular causes of mortality among cancer patients in the US since the turn of the century.

Results of the study suggest IHD was the leading cause of CVD-specific death, but the attributable fraction of deaths from IHD had decreased during the study period while the proportion of deaths attributable to hypertensive disease increased throughout the duration of the study period.


3. Hormone Shift in Menopause Contributes to Cardiovascular Risk in Aging Women

A new study of more than 200 women in Europe suggests hormonal changes during menopause could explain up to 10% of the increase in LDL-C associated with the menopause transition. 

Results of the study suggest the hormonal shift in 17β-oestradiol and FSH levels among women transitioning from perimenopause to early postmenopause was associated with proatherogenic circulating metabolome alterations, with these metabolite shifts were partially ameliorated with HRT.


4. Don't Miss a Beat: Interpreting New Heart Failure Guidelines

The new ACC/AHA/HFSA 2022 heart failure guidelines represent a monumental and historic set of evidence-based recommendations.

In this episode of Don’t Miss a Beat, hosts Stephen Greene, MD, and Muthiah Vaduganathan, MD, MPH, breakdown the joint guidelines, provide perspective on the recommendations from the viewpoint of practicing cardiologists, and juxtapose the recommendations made in the new guidelines against those made within the ESC 2021 heart failure guidelines.


American Heart, Stroke Associations Release Updated Guidance for Intracerebral Hemorrhage

On May 17, the American Heart Association and the American Stroke Association released new guidelines for management of intracerebral hemorrhage.

An 80-page document broken down into 9 sections, the guidelines were created to replace the organizations’ 2015 intracerebral hemorrhage guidelines.

6. Q&A on SCAI's 2022 PFO Guidelines, with Clifford Kavinsky, MD, PhD

At the start of the Society for Cardiovascular Angiography and Interventions (SCAI) 2022 annual meeting, the SCAI released their first comprehensive guideline for the management of patent foramen ovale.

To learn more about the recommendations made in the guideline and how they might impact practice, 

 reached out to writing group chair Clifford Kavinsky, MD, PhD, to take part in a Q&A on the 15-page document.





Our cardiology month in review spotlights the most popular content from the past month. This month's top articles include news from DELIVER, new guidelines for ICH and PFO, and a juxtaposition of international heart failure guidelines. 

Cardiology Month in Review: May 2022

An analysis of up to 21 years of follow-up data from the Diabetes Prevention Program Outcomes Study (DPPOS), results of the study indicate use of metformin and lifestyle intervention were associated with a reduction in risk of type 2 diabetes, but neither reduced risk of major adverse cardiovascular events during follow-up.

“The fact that neither a lifestyle intervention program nor metformin led to a decrease in cardiovascular disease among people with prediabetes may mean that these interventions have limited or no effectiveness in preventing cardiovascular disease, even though they are highly effective in preventing or delaying the development of Type 2 diabetes,” said DPPOS writing group chair Ronald Goldberg, MD, a senior faculty member and co-director of the Diabetes Research Institute Clinical Laboratory at the University of Miami’s Miller School of Medicine, 

Supported by grants from the US Centers for Disease Control and Prevention, the American Heart Association and several divisions of the National Institutes of Health, including the National Institute of Diabetes and Digestive and Kidney Diseases, DPPOS is a follow-up of the original Diabetes Prevention Program study, which was launched in 1996 with the intent of examining the effect of lifestyle intervention or treatment with metformin to prevent or delay type 2 diabetes in high-risk individuals with prediabetes.

In the original Diabetes Prevention Program, 3234 participants with impaired glucose tolerance were assigned to metformin 850 mg twice-daily, intensive lifestyle intervention, or placebo. As part of DPPOS, follow-up of these patients continued and they were offered a less intensive group lifestyle intervention and unmasked metformin was continued in the metformin group. Overall, DPPOS contained 1073 patients randomized to placebo, 1082 randomized to metformin, and 1079 randomized to intensive lifestyle intervention, with a time-weighted mean follow-up of 21 years.

The primary outcome of interest was first occurrence of nonfatal myocardial infarction, stroke, or cardiovascular death adjudicated by standard criteria. The study also included an extended cardiovascular outcome that included the primary outcome or hospitalization for heart failure or unstable angina, coronary or peripheral revascularization, coronary heart disease diagnosed by angiography, or silent myocardial infarction by ECG.

Upon analysis, results indicated the reduction in development of type 2 diabetes observed in the original Diabetes Prevention Program study were sustained through the follow-up period. When assessing the risk of the [primary outcome, results suggested neither use of metformin (HR, 1.03 [95% CI, 0.78-1.37]; 

=.81) nor lifestyle intervention (HR, 1.14 [95% CI, 0.87-1.50]; 

=.34) were associated with a reduction in the primary outcome compared with placebo therapy. Investigators pointed out risk factor adjustment did not change these results.

When assessing major cardiovascular event components, results suggested there were fewer nonfatal strokes in the metformin group than in the placebo group, with no significant difference in rates (HR, 0.57 [95% CI, 0.31-1.06]; 

=.07), but the opposite trend was observed for the lifestyle intervention group (HR, 1.42 [95% CI, 0.87–2.30];

=.16). Further analysis demonstrated there was no effect of either intervention on the extended cardiovascular outcome.

“It’s important to note that most study participants also received treatment with cholesterol and blood pressure medications, which are known to reduce CVD risk. Therefore, the low rate of development of cardiovascular disease found overall may have been due to these medications, which would make it difficult to identify a beneficial effect of lifestyle or metformin intervention,” Goldberg added. “Future research to identify higher risk subgroups is needed to develop a more targeted approach to cardiovascular disease prevention in people with prediabetes and type 2 diabetes.”

Effects of Long-term Metformin and Lifestyle Interventions on Cardiovascular Events in the Diabetes Prevention Program and Its Outcome Study,

Data from an analysis of follow-up data from the landmark DPPOS study provide insight into the apparent lack of cardiovascular risk reduction provided to patients with prediabetes from metformin and lifestyle interventions.

Metformin, Lifestyle Changes Not Enough to Stave off CVD Risk in T2D

A great deal has changed since the beginning of the COVID-19 pandemic in early 2020. The first year, we played catch-up trying to figure out how to get a handle on the rapidly deteriorating situation. While focusing on the respiratory consequences of COVID-19 infection clinicians were slow to recognize trends in other key healthcare metrics.

Pre-pandemic trends in the most severe form of heart attack, ST Elevation Myocardial Infraction (STEMI) had remained steady and predictable with heart disease rates rising and remaining the number one cause of death for Americans. During the pandemic clinicians noticed some unusual changes in the frequency of patients seeking care leading to percutaneous coronary interventions (PCI) for acute STEMI.

While it is known now that COVID-19 has clear effects on the cardiovascular system the pandemic itself had an unexpected effect on PCI. Clinicians began to notice that fewer patients were presenting with STEMI which led to fewer coronary interventions. Manoj Thangam, MD, and colleagues at Ascension Health System sought to determine both the PCI trends during the pandemic and the reasons behind them. They presented their findings at the Society for Cardiovascular Angiography & Interventions (SCAI) 2022 scientific sessions in Atlanta, GA.

The authors pulled data from several centers that monitor percutaneous interventions (PCI) for STEMI in an effort to compare predicted PCI volume before widespread COVID-19 prevalence and during documented surges. The prevailing trend prior to April of 2020, the first COVID surge, was a steady increase in STEMI and PCI in keeping with an overall increase in the prevalence of coronary heart disease in the United States.1 April 2020 then saw a dramatic decrease in STEMI and PCI with a subsequent rise until December 2020, the second surge.

 The expected number of cases per month has yet to recover from pandemic levels.

While the study itself does not point clearly to the cause for this decrease and failure to reach expected PCI and STEMI rates now that widespread immunity to COVID 19 has been achieved there are several possibilities to consider.

“Despite STEMI rates rising, we’ve never gotten back to our pre-COVID baseline which probably tells us there is still hesitation to come to the hospital despite having a major heart attack,” Thangam said.

Even though a hesitancy to come into the hospital for chest pain undoubtedly plays a part in the reductions in coronary interventions, the authors concede that continued analysis is necessary as well as consideration for the ramifications of this trend. If the number of acute coronary syndromes (ACS) are, in fact, continuing to rise and people are simply not going to the hospital the authors suspect a subsequent rise in mortality, heart failure, and other morbidities related to coronary disease in the aftermath of the pandemic.

Other causes should also be entertained. Further study should look into all-cause mortality during the COVID-19 pandemic. It has been assumed that a large number of deaths due to COVID-19 over the last 2 years were related to the respiratory complications so often cited in reports. The truth is that cardiovascular complications related to COVID-19 are well described and that mortality related to viral infection is likely multifactorial.

Although respiratory failure is common in serious COVID-19 infection, long-term cardiac damage may lead to more ACS, STEMI, and PCI down the road. We must ask the tough questions. Are more people dying at home of coronary heart disease? Are more people suffering heart attacks that are non-fatal and simply brushing them off?

It is essential that clinicians continue to encourage patients to come into the hospital for chest pain and exertional dyspnea, especially if they have risk factors for coronary heart disease. The risk of dying or long-term morbidity is high. This is not just about numbers—it is about quality of life and fear. The authors of this abstract are right to highlight the impact of global media campaigns telling people to stay home as a potential reason for reduced PCI and STEMI volumes. I suspect however, as with most emerging evidence, that this reasoning is only the tip of the iceberg.

https://www.jscai.org/article/S2772-9303(22)00063-1/fulltext

Data presented at SCAI 2022 detail trends in PCI during the COVID-19 pandemic. In this column, Dr. Gregory Weiss provides perspective on these trends and what it may mean for cardiologists going forward. 