#463 Tofurkey-cakes: A Hypertension Triple Pill, Arm Position & BP, early TAVR, Liberal vs Restrictive Transfusions, New Periop Guidelines

November 25, 2024 | By Rahul Ganatra

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Join us as we review recent practice-changing articles on a new triple pill for hypertension, how arm position affects blood pressure, early TAVR for asymptomatic patients with severe AS, liberal versus restrictive transfusion strategy in patients with acute brain injury, and a quick overview of the 2024 ACC/AHA perioperative medicine guidelines. Fill your brain hole with a delicious stack of tofurkey cakes! Featuring Paul Williams (@PaulNWilliamz), Rahul Ganatra (@rbganatra), Jen DeSalvo (@drjendesalvo), and Matt Watto (@doctorwatto).

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Show Segments

• Intro, disclaimer
• A new triple pill for hypertension
• How arm position affects blood pressure
• Early TAVR for asymptomatic patients with severe AS
• Liberal versus restrictive transfusion strategy in patients with acute brain injury
• A quick overview of the 2024 ACC/AHA perioperative medicine guidelines
• Outro

Hotcake #1 Triple Pill for HTN (Watto)

Rodgers A, et al; GMRx2 Investigators. Efficacy and safety of a novel low-dose triple single-pill combination of telmisartan, amlodipine and indapamide, compared with dual combinations for treatment of hypertension: a randomised, double-blind, active-controlled, international clinical trial. Lancet. 2024 Oct 19;404(10462):1536-1546.

What was the research question? Does GMRx2 (a triple pill containing amlodipine, telmisartan, and indapamide) safely and effectively reduce home BP readings at 12 weeks compared with dual therapy in adults with hypertension? 

Why is this study important? Controlling blood pressure is limited by side effects, adherence, polypharmacy, and patient misconceptions of blood pressure treatment. Further, most people require at least two medications, and many require three or more blood pressure medications (SPRINT, 2015). Several guidelines now recommend dual therapy, including with single-pill combinations (ESH, 2024; ISH, 2020), which in the US are often included in insurance formularies.

How was the study done? This was an international, multicenter, double-blind, randomized controlled trial. After a 4-week single-blind, active run-in on half-dose triple pill (telmisartan 20 mg, amlodipine 2·5 mg, and indapamide 1·25 mg), patients were randomized 2:1:1:1 to take identical capsules of GMRx2 or each of three possible dual-therapy combinations. Patients continued on half-dose medications until week 6 and then increased to full-dose from week 6 to 12. Patients performed home BP monitoring.

Who were the patients? 1,385 relatively healthy, nonpregnant adults with hypertension were included. Patients were excluded if they were four or more antihypertensives or had cardiovascular disease, uncontrolled diabetes, eGFR <60 mL/min, substance use disorders,  worked night shifts, or had an arm circumference too large or too small for the home BP equipment.

Top-line results: This was a positive trial: a once-daily triple pill (GMRx2) containing amlodipine-telmisartan-indapamide lowered home systolic blood pressure at 12 weeks 2 – 6 mm Hg more than dual-therapy combinations with a CCB-diuretic, ARB-diuretic, or CCB-ARB. Serious adverse events were similar among the groups, but symptomatic hypotension occurred in 32 patients (6%) on GMRx2 vs 1-4% of patients on dual therapy. 

Learning points & Limitations: The use of an active run-in period tends to screen out patients who don’t adhere to the trial protocol or who experience side effects – for this reason, this trial is vulnerable to underestimating adverse effects. 

Bottom line: I love combination therapy for hypertension, and so do my patients. Clinical inertia and patient reluctance to take multiple medications are barriers to achieving blood pressure targets, but combination pills help overcome this hurdle. This study reassures us that a triple combination with amlodipine-telmisartan-indapamide is safe and effective at lowering blood pressure in healthy, nonpregnant adults. Still, the population was highly selected and patients had to tolerate an active run-in, which limits generalisability. I’d like to see further studies in patients with more severe hypertension, known cardiovascular disease, uncontrolled diabetes, CKD, and obesity to help guide real-world practice.   

Hotcakes rating: 3.5 tofurkey cakes

Further reading:

• Editorial in the Lancet (Antonopoulou, 2024)

Hotcake #2 Arm Position and BP (Paul)

Liu H et al. Arm position and blood pressure readings: The ARMS crossover randomized clinical trial. JAMA Internal Medicine. 2024 Oct 7; 5213: E1-E7. DOI: 10.1001/jamainternmed.2024.5213. PMID: 39373998. 

What was the research question? How do different arm positions (arm supported on a desk, hand supported on lap, or arm unsupported at the side) affect blood pressure measurement?  

Why is this study important? Hypertension is a leading cause of preventable cardiovascular disease and mortality, but blood pressure measurement in clinical practice is frequently inaccurate. Underestimation of blood pressure may result in untreated disease, while overestimation may result in polypharmacy and the adverse effects associated with blood pressure medications.

How was the study done? This was a randomized crossover trial with 133 participants, each serving as their own control. Four triplicate blood pressure measurements were obtained in a random order (desk, lap, side, and desk again, to account for intrinsic blood pressure variability) 

Who were the patients? Participants were adults (mean age in the 50s) recruited using BP screenings, direct mailings to previous research participants, informational brochures, and physician referrals.

Top-line results: This was a positive study: arm positioning was associated with differences in measured blood pressure. Systolic and diastolic pressures measured with the arm in the lap or at the side were higher by 3 – 7 mm Hg than blood pressures measured with the arm appropriately supported with the midcuff at heart level.  

Learning points & limitations: Despite uneven allocation across groups in this small study, ineffective randomization is unlikely to threaten these results. These results also make mechanistic sense: we might expect a dependent arm to have higher pressure than a supported arm due to hydrostatic pressure from gravity and vasoconstriction from venous pooling.

Bottom line/Hotcakes rating -4 / 5 tofurkey cakes, with gravy

Hotcake #3 Early TAVR (Rahul)

Généreux P, Schwartz A, Oldemeyer JB, et al. Transcatheter aortic-valve replacement for asymptomatic severe aortic stenosis. N Engl J Med. Published online October 28, 2024:NEJMoa2405880.

What was the research question? Among low-risk patients with asymptomatic severe aortic stenosis (AS), does early TAVR reduce death, stroke, and CV hospitalizations compared with clinical surveillance? 

Why is this study important? The population-level burden of severe AS in the United States is high: the annual incidence is ~50 cases / 100,000 patient-years, and the prevalence over age 75 is ~3.5%. Current guidelines recommend aortic valve replacement for patients with severe AS and symptoms, LVEF <50%, a positive stress test, or another indication for cardiac surgery. Whether asymptomatic patients might benefit from earlier valve replacement is unknown. 

How was the study done? Patients at 75 sites in the US and Canada were randomized 1:1 to undergo early transfemoral TAVR with an Edwards Sapien 3 valve, or clinical surveillance alone, which consisted of follow-up visits every 6 to 12 months.

Who were the patients? The trial included 901 patients (mean age 76; essentially everybody was white; predicted 30-day post-operative mortality risk of 1.8% via STS risk score, LVEF 67%) with severe AS and anatomy favorable for TAVR. These were generally low-risk and highly functional patients: asymptomatic status was confirmed by a negative treadmill stress test in 90% of patients! 

Top-line results: This was a positive study: over a median follow-up of 3.8 years, compared with clinical surveillance alone, early TAVR led to an 18.5% absolute (50% relative) reduction in a composite outcome of death, stroke, or unplanned cardiovascular hospitalization. This was entirely driven by a 20% absolute risk reduction in cardiovascular hospitalizations, an outcome which included conversion to TAVR within 6 months in the surveillance group. There were no differences in stroke or death. 

Learning points & limitations: Defining conversion to TAVR within 6 months in the clinical surveillance group as an unplanned CV hospitalization is a major source of bias towards this being a positive study. There were no differences in death, stroke, new AF, or LVEF. Interpretation of the two secondary outcomes that suggested a benefit of early TAVR (symptom reduction and improved TTE surrogates of LV/LA health) is really limited by the open-label nature of the trial. In particular, myocardial remodeling in AS is thought to be reversible after TAVR, so this study does not suggest a clear benefit to early TAVR. 

Bottom line/Hotcakes rating: While early TAVR in asymptomatic patients is probably safe, it is not clear that it improves any patient-centered outcomes over just waiting until an indication for valve replacement to develop.

2 / 5  tofurkey croquettes

Hotcake #4 Liberal Transfusion after Acute Brain Injury (Jen DeSalvo)

Taccone FS et al; TRAIN Study Group. Restrictive vs Liberal Transfusion Strategy in Patients With Acute Brain Injury: The TRAIN Randomized Clinical Trial. JAMA. 2024 Oct 9. doi: 10.1001/jama.2024.20424. Epub ahead of print. PMID: 39382241. 

What was the research question? Does a liberal transfusion strategy (transfusing for Hgb <9 g/dL), compared with a restrictive transfusion strategy (transfusing for Hgb <7 g/dL), improve neurologic outcomes among patients with acute brain injury and anemia?

Why is this study important? Anemia has been associated with worse outcomes among patients with acute brain injury, but the optimal transfusion strategy in this patient population remains unknown. 

How was the study done?  In this international, multi-center, open-label, clinical trial, adults admitted to an ICU with acute brain injury (traumatic brain injury, subarachnoid hemorrhage, or intracerebral hemorrhage) with hemoglobin <9 g/dL, a Glasgow Coma Scale score of ≤13, and an expected ICU LOS >3 days were randomized to a liberal or restrictive transfusion strategy.

Who were the patients?  850 patients (mean age in low 50s; ~60% had traumatic brain injury; median hemoglobin at randomization of 8.5 g/dL) were randomized to receive transfusions according to a liberal or restrictive strategy for up to 28 days. Patients in the liberal group received a median of 2 units of blood, and those in the restrictive group received a median of 0 units of blood.

Top-line results: This was a positive trial: critically ill patients with acute brain injury and anemia randomized to the liberal strategy group had a lower rate of unfavorable neurologic outcomes compared with those in the restrictive arm at 180 days: 62.6% vs.72.6%; RR 0.86 (0.79-0.94). Patients randomized to a liberal strategy also had fewer cerebral ischemic events :8.8% vs 13.5%.

Learning points & Limitations: These findings are at odds with previous research, including the recently published HEMOTION trial, which found that a liberal transfusion strategy (defined as transfusing for a hemoglobin of <10 g/dL) did not improve neurologic outcomes compared with a restrictive strategy among a somewhat narrower population of patients with TBI. One possible explanation is that the TRAIN trial did not adjust for differences in baseline prognosis, which could be a source of bias towards a positive outcome in this study. Although these results are mechanistically plausible, liberal transfusion is a costly strategy, with about 2.5x more blood transfused in total in the liberal group. Further research is needed to clarify optimal transfusion thresholds in this population.  

Bottom line: This study suggests that a liberal transfusion strategy in patients with acute brain injury and anemia might improve neurologic outcomes and encourages me to transfuse more liberally in patients with acute brain injury. Hopefully the results of other ongoing studies will clarify the optimal transfusion threshold in patients with acute brain injury.

Hotcakes rating: 4 / 5

Further reading:

• HEMOTION trial (Turgeon, 2024)
• MINT trial (Carson, 2023) covered on #424 Hotcakes by Rahul Ganatra 
• Effect of Erythropoietin and Transfusion Threshold on Neurological Recovery After Traumatic Brain Injury: A Randomized Clinical Trial | Bleeding and Transfusion | JAMA | JAMA Network

Hot take #1 Periop Update (Rahul)

Thompson A, Fleischmann KE, Smilowitz NR, et al. 2024 AHA/ACC/ ACS/ASNC/ HRS/SCA/ SCCT/SCMR/SVM guideline for perioperative cardiovascular management for noncardiac surgery: a report of the american college of cardiology/american heart association joint committee on clinical practice guidelines. Circulation. 2024;150(19).

Summary: The ACC/AHA just published new guidelines for perioperative management of patients undergoing noncardiac surgery, updating the last guidelines from 2014. Here are some highlights: 

• Use validated risk calculators to identify patients at elevated risk for perioperative MACE (RCRI, Gupta, etc)
• Use the Duke Activity Status Index (DASI) to assess functional capacity for patients at elevated perioperative risk.
• Consider measurement of preoperative BNP in patients with poor or unclear functional capacity if further testing might affect decision-making. Measuring troponins is a reasonable alternative but has a weaker evidence base.
• Pursue stress testing ONLY in selected patients with elevated perioperative risk, poor or unknown functional capacity, and who have an indication for stress testing independent of the planned surgery (for example, angina or suspicion of left main or severe multivessel disease). 
• Coronary CTA is a reasonable alternative to stress testing but may overestimate risk.
• Continue antihypertensives for most patients through surgery, unless they have low-normal blood pressure, to avoid perioperative hypertension.
• Stop SGLT2 inhibitors 3-4 days before surgery to avoid ketoacidosis.
• Consider checking troponins post-operatively in high risk patients to identify myocardial injury after noncardiac surgery (MINS), which is a poor prognostic marker and identifies patients who may benefit outpatient follow-up for risk factor optimization.

Bottom line: The updated guidelines contain new recommendations on determination of functional capacity (using DASI), the role of troponin and BNP measurement to aid in risk stratification, and on perioperative management of antihypertensives and other medications. It is likely that these guidelines will result in fewer and more judicious use of preoperative stress testing, reflecting the absence of clear evidence that they improve outcomes.

Further reading:

• 2024 Perioperative Cardiovascular Management for Noncardiac Surgery Guideline-at-a-Glance (JACC, 2024)

Links

Links are included in the show notes above.

Goals

Listeners will review recent practice-changing articles and medical news.

Learning objectives

After listening to this episode listeners will…

1. Evaluate the safety and efficacy of a new triple combination pill for hypertension
2. Learn how arm position affects blood pressure readings
3. Evaluate the risks and benefits of early TAVR in asymptomatic patients with severe AS
4. Decide on a liberal vs restrictive transfusion strategy for patients with acute brain injury
5. Discuss key changes from the 2024 perioperative medicine guidelines

Disclosures

The Curbsiders report no relevant financial disclosures. 

Citation

Ganatra RB, DeSalvo J, Williams PN, Watto MF. “#463 Tofurkey-cakes: A Hypertension Triple Pill, Arm Position & BP, early TAVR, Liberal vs Restrictive Transfusions, New Periop Guidelines”. The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list Final publishing date, November 25, 2024.