Switching from hydrochlorothiazide to chlorthalidone in hypertension: any benefit?

Insights by Alta Schutte

Diuretics are a key tool in the arsenal to treat high blood pressure. Where earlier studies suggest better cardiovascular outcomes with the now commonly used diuretic, chlorthalidone, more recent large-scale observational studies point to no cardiovascular benefit when compared to hydrochlorothiazide. The Diuretics Comparison Project (DCP) therefore compared the effectiveness of these two common diuretics in reducing major cardiovascular outcomes or non-cancer deaths. They included 13,523 veterans aged 65 years and older, with a most recent systolic blood pressure higher or equal to 120 mmHg, and who were already taking hydrochlorothiazide – 95% were prescribed 25 mg. These patients were randomised to switch to chlorthalidone (n=6,756) or to continue using hydrochlorothiazide (n=6,767) over a median follow-up of 2.4 years.

At the AHA 2022 meeting in Chicago, Areef Ishani and co-authors reported similar blood pressure control and no benefit in reducing major cardiovascular outcomes or non-cancer deaths (p=0.40) when switching from hydrochlorothiazide to chlorthalidone at doses commonly used in clinical practice (25 mg hydrochlorothiazide and 12.5 mg chlorthalidone). There was also no difference in stroke, myocardial infarction, hospitalisation due to heart failure or other cardiovascular outcomes. In a priori subgroup analyses, no differences were reported either, except for a small group who had a history of myocardial infarction or stroke, where those taking chlorthalidone had a reduced risk of cardiovascular outcomes by an average of 27% (p=0.035). As for adverse events, hypokalaemia occurred more frequently in the chlorthalidone group (6% vs 4.4%; p<0.001).

This pragmatic trial reported findings in ‘real-life’ clinical practice, where 87% were prescribed two or more antihypertensives. The potential bias of a switching trial, where all were already using hydrochlorothiazide at inclusion, should be carefully investigated. An expected but key limitation is the inclusion of only 3% women, which may introduce sex-specific bias.

Does immediate ECMO make a difference in cardiogenic shock?

Insights by Susanna Price

Extracorporeal membrane oxygenation (ECMO) is increasingly used as a circulatory support strategy for patients with cardiogenic shock (CS), but high-quality evidence to support/guide its use is lacking. The ECMO-CS trial represents the first randomised clinical trial comparing immediate implementation of ECMO vs early conservative therapy in patients with CS. Undertaken in four centres within the Czech Republic, September 2014 to January 2022, 117 patients with either rapidly deteriorating (SCAI D/E) or severe (SCAI D with defined haemodynamic/metabolic parameters) CS were randomised: 58 to immediate ECMO and 59 to early conservative therapy, which consisted of standard critical care support with the possibility of crossover to ECMO in the case of deterioration. The mean age was 65 years (73.5% male), and no routine venting/offloading strategy was utilised. The primary endpoint was a composite of death from any cause, resuscitated circulatory arrest and implantation of another mechanical circulatory support device at 30 days.

The main finding was no difference in the composite primary endpoint between the two groups, which occurred in 63.8% of the immediate ECMO group vs 71.2% of the conservative group (HR 0.72; 95% CI 0.46 to 1.12; p=0.21), however, 39% of the early conservative strategy group crossed over to receive ECMO. All-cause mortality and serious adverse events other than primary endpoints were comparable between the two groups. Thus, there appears to be no benefit from implementing immediate ECMO in rapidly deteriorating or severe CS, compared with an early conservative strategy of conventional critical care that permits use of ECMO in the event of worsening haemodynamic and metabolic status.

EMPA-KIDNEY: The ever-expanding role of SGLT-2 inhibitors

Insights by Michael Papadakis

SGLT-2 inhibitors were initially designed for glucose lowering in diabetic patients. Subsequently, they were found to reduce major cardiovascular outcomes in patients with diabetes and CVD. The role of SGLT-2 inhibitors then expanded when they reduced hospitalisation and CV death in heart failure trials, regardless of the presence or absence of diabetes. Similarly, the DAPA-CKD study demonstrated that in patients with CKD, dapagliflozin reduced the risk of kidney function decline or death from renal or CV causes, irrespective of diabetes status.

The EMPA-KIDNEY trial looked at a broad range of patients with CKD at risk of progression, including patients with an eGFR as low as 20 ml/min/1.73 m2 but also patients with relatively normal/mildly reduced eGFR and significant proteinuria. Patients were randomised to empagliflozin 10 mg once daily or placebo. A third were females and more than half (54%) did not have diabetes. A 28% reduction in the primary outcome of kidney disease progression or CV death was observed that was predominantly driven by renal outcomes. All-cause hospitalisations were reduced by 14%, which is substantial considering an average hospitalisation rate of 29 per 100 patient-years and a rate as high as 49 per 100 patient-years with prior CVD. There was a 16% reduction in CV death or heart failure hospitalisation; however, this did not reach significance due to the low absolute number of CV events.

EMPA-KIDNEY further expands the indications of SGLT-2 inhibitors, suggesting they should be considered early in a wide range of patients with kidney disease. The million-dollar question remains – how do they achieve their benefits?

ENHANCE-AF: A digital support tool can improve shared decision-making for patients and clinicians

Insights by David Duncker

The ENHANCE-AF trial was a multicentre, randomised, controlled, double-arm, open-label trial, which compared the effectiveness of a shared-decision making pathway vs usual care in reducing decisional conflict in patients considering anticoagulation in AF stroke prevention. The shared decision-making process involved a digital tool particularly tailored for use by patients with low health literacy and provided in English, but also in Spanish.

Patients enrolled were 18 years or older, had a diagnosis of non-valvular AF and had a CHADS-VASc score of at least 1 for men or at least 2 for women. Participants were randomised 1:1 to shared-decision making pathway vs usual care. The digital tool included a 4-minute animated video, interactive FAQs, a reinforcing quiz, a worksheet for the clinician visit and a digital clinician guide. The primary endpoint was a 16-item decisional conflict scale at 1 month after the index visit. In total, 1,001 participants were enrolled at five US sites between December 2019 and August 2022. Their mean age was 69 years and 60% were male.

The primary endpoint achieved a 7-point difference in median scores between the two arms (16.4 vs 9.4; p=0.007) at 1 month, highlighting that with this novel and digital tool, the shared decision-making pathway achieved significantly lower decisional conflict.

ISCHEMIA-EXTEND – were there any surprises with long-term follow-up?

Insights by Stephan Achenbach

The original ISCHEMIA trial published in 2020 recruited 5,179 patients with a positive stress test for ischaemia and, in patients without renal failure, presence of at least one stenosis > 50% and absence of left main stenosis on CT angiography. In all patients, high-dose statin therapy was initiated and patients were then randomised to an initially invasive strategy, with invasive coronary angiography and potentially revascularisation or to a conservative strategy with initial medical management. In the invasive arm, 80% of patients underwent revascularisation as compared to 23% in the invasive arm and the initial 3.2-year results showed no difference in mortality, but better control of angina and higher quality of life in patients who had been randomised to the invasive arm.

Now, follow-up was extended to a median of 5.7 years, but the only outcome parameter was mortality. No difference in total mortality between the two arms was found (13.4%/7 years in the conservative arm vs 12.7%/7 years in the invasive arm (adjusted HR 1.0; 95% CI 0.85 to 1.18). Interestingly, cardiovascular mortality was lower in the invasive arm as compared to the initially conservative arm (6.4% vs 8.6%, HR 0.78; 95% CI 0.63 to 0.96), but this was offset by higher non-cardiovascular mortality. Data on angina and quality of life were not collected.

IRONMAN – Ironing out heart failure treatment

Insights by Marco Metra

Iron deficiency (ID) is a common comorbidity of heart failure (HF) patients. Data regarding the long-term effects of iron supplementation in outpatients were lacking. This was addressed in IRONMAN (Effectiveness of Intravenous iron treatment vs. standard care in patients with heart failure and iron deficiency), a prospective multicenter open-label, blinded-endpoint trial conducted across 70 UK hospitals enrolling 1,137 adults with HF, LVEF <45% and ID, only 16% hospitalized. Patients were assigned to intravenous ferric derisomaltose or not, in addition to standard HF care. Additional iron administrations were allowed if ID returned. During a median follow-up of 2.7 years, the primary outcome of HF hospitalizations and cardiovascular death occurred in 22.4 vs 27·5 per 100 patient-years in the ferric derisomaltose vs the usual care group (rate ratio [RR] 0·82, 95% confidence interval [CI] 0·66 to 1·02; p=0·070). Consistent with AFFIRM-AHF, statistical significance was reached in a prespecified COVID-19 sensitivity analysis, RR, 95%CI, 0,76; 0.58 to 1.00; p=0·047, the reduction in the primary endpoint was driven by a reduction in HF hospitalizations and quality of life was also improved. Safety of iron therapy was also confirmed with fewer serious cardiac adverse events and no increase in infections or other untoward events with ferric derisomaltose. Compared with AFFIRM-AHF, these data were obtained with a longer follow-up and mainly in outpatients.

IRONMAN investigators must be praised for their commitment to a major unmet question of HF treatment, long-term efficacy and safety of ID correction, paving the way for better treatment of our patients.

PRECISEly which strategy is best in suspected CAD?

Insights by Eva Prescott

In chronic coronary syndrome, good rule-out algorithms and precise non-invasive tests are needed to avoid unnecessary tests, catheterisation and costs. The PRECISE (Prospective Randomized Trial of the Optimal evaluation of Cardiac Symptoms and Revascularization) trial, funded by HeartFlow, evaluated a precision care strategy compared with usual testing. The precision strategy consisted of quantitative risk stratification using the PROMISE Minimal Risk Score to select deferred testing for the lowest risk participants or coronary computed tomographic angiography (cCTA) as the initial test for all others, with selective fractional flow reserve (FFRCT) for intermediate stenoses. Usual testing participants received either initial stress testing or cardiac catheterisation, according to the clinician’s decision.

In total, 2,103 patients were randomised across North America and Europe. In the precision strategy arm, 174 (16%) had testing deferred vs 68 (7%) in the usual testing arm and 4 (0%) went directly to ICA vs 101 (10%) in the usual testing arm. Over a median follow-up of 11 months, the primary endpoint of all-cause death, MI or ICA without obstructive CAD was met in 44 (4.2%) in the precision strategy arm and in 118 (11.3%) in the usual testing arm (p<0.001). The difference was driven by a difference in ICA without obstructive CAD (2.6% vs 10.2%), with no significant differences in death or MI. Importantly, there were no events among the 174 participants who had testing deferred. More patients in the precision strategy arm were revascularised (97 vs 54; p<0.01). Angina control was good in both groups, but more patients in the precision strategy group were started on lipid-lowering or antiplatelet medication.

The study provides important confirmation that deferred testing in low-likelihood patients is safe. The high proportion of patients referred directly to ICA is likely driving the higher rate of ICA with no obstructive CAD. The study design does not allow for a direct comparison between a cCTA/FFRCT guided strategy and other non-invasive testing. However, further data from the trial may elucidate whether cCTA/FFRCT leads to less downstream testing and higher cost-effectiveness.

Progress for early ablation compared to antiarrhythmic drug treatment revealed in the PROGRESSIVE-AF study

Insights by Emma Svennberg

The randomised controlled PROGRESSIVE-AF trial, presented by Professor Jason Andrade at AHA 2022 and simultaneously published in the New England Journal of Medicine, assessed if early catheter ablation could prevent progression of atrial fibrillation (AF) from paroxysmal to persistent compared to antiarrhythmic drug therapy.

The 303 patients enrolled in the study were previously naïve to rhythm intervention, relatively young (average 58 years) with few co-morbidities and had been diagnosed with AF for 1 year. Participants were randomised to either catheter ablation by cryoballoon or to antiarrhythmic drug therapy. Heart rhythm after the intervention was monitored by an implantable loop recorder.

The primary endpoint was the occurrence of persistent atrial tachyarrhythmias (lasting >7 days or requiring cardioversion) including AF, atrial flutter or other atrial tachycardias after the initial blanking period of 3 months as measured by ILR after 3 years. Despite the enrollment of a relatively healthy population, the primary outcome showed a significant reduction of AF progression in the group randomised to catheter ablation as compared to antiarrhythmic drug therapy, with a reduction in incidence of 75% (HR 0.25; 95% CI 0.09 to 0.70). The number needed to treat was 18. Overall, persistent arrhythmias occurred in 1.9% of the ablated patients compared to 7.4% in the group receiving pharmacological intervention, with long persisting episodes (median 15.8 days). The trial also showed positive outcomes for the prespecified secondary outcomes of any atrial tachyarrhythmia recurrence, quality-of-life outcomes and reduction in hospitalisations in the group randomised to ablation, with fewer adverse events in the catheter ablation group. As pointed out by discussant Professor Carina Blomström-Lundqvist, a drawback of the study was that AF burden was not monitored prior to rhythm intervention, hence a progression of more paroxysmal episodes of AF could not be assessed.

In summary, early intervention with catheter ablation showed a significant reduction in incidence of AF progression as compared to pharmacological treatment.

The PROMINENT study: Disappointing important results

Insights by Francois Mach

Diabetic patients at high cardiovascular risk with elevated triglycerides and lower HDL did not benefit from pemafibrate to lower cardiovascular outcomes in PROMINENT, a very well conducted placebo-controlled randomised clinical trial. Side effects included high prevalence of venous thrombosis as well as renal events in the pemafibrate-treated group.

These results were surprising and disappointing to many from both a scientific and clinical perspective. However, based on the ensemble of clinical trials we have today with various fibrates, we cannot expect cardiovascular benefit in patients who are well treated with statins. The signal for potential benefit with pemafibrate for non-alcoholic fatty liver disease merits follow-up studies.

Treatment with fibric acid derivatives does have a role to play in the control of extreme hypertriglyceridaemia to lower the risk of pancreatitis. Cardiovascular risk of elevated triglyceride-rich lipoproteins is still under exploration with studies targeting apoC3 or ANGPTL3.

The discordance between the subsidiary analyses of prior fibrate trials and the PROMINENT results reminds us once again that studies of subgroups cannot replace a placebo-controlled randomised clinical trial.

RESPECT-EPA – CV benefit or more controversy?

Insights by Nicolle Kraenkel

With the availability of effective LDL-lowering drugs, residual risk for cardiovascular events now needs to be targeted. Omega-3-polyunsaturated fatty acids are potential candidates, especially eicosapentaenoic acid (EPA), as it can lower triglycerides, support the resolution of inflammation and counteract platelet aggregation. Several prior studies using different designs, molecules and study populations have yielded controversial results.

RESPECT-EPA tested a 1.8 g daily dose of EPA on top of established statin therapy in patients with chronic coronary artery atherosclerotic disease compared with statin therapy alone. This was an open-label randomised and controlled trial in 2,506 patients with low blood EPA levels at inclusion (EPA <0.4-fold of arachidonic acid blood levels). Over a follow-up of 4 years, there was a borderline significance for EPA reducing the primary endpoint, a composite of cardiovascular death, nonfatal myocardial or cerebral infarction and coronary revascularisation. There was a significantly higher rate of gastrointestinal disorders and new-onset atrial fibrillation in the EPA arm.

The study, while being underpowered, adds to current understanding that purified EPA might potentially be effective in secondary prevention to address residual cardiovascular risk. In line with previous observations, the effect appears to be linked to effectively raising EPA levels in persons with initially low EPA blood concentrations. Future studies need to clarify the suitability of the dose, the inflammatory status of the population and whether these data from a Japanese population can be verified in populations with different genetic background and diets. Increased risk of atrial fibrillation – also observed previously – needs to be monitored.

No need to transform your practice from furosemide to torsemide based upon TRANSFORM-HF

Insights by Wilfried Mullens

The primary objective of the randomized TRANSFORM-HF trial was to determine whether long-term oral torsemide treatment would be superior to furosemide in reducing all-cause mortality among patients hospitalized for heart failure. Rationale to perform the trial was that torsemide would have a better bio-availability, longer duration of action and some anti-fibrotic effects. It was a very pragmatic event-drive trial with simple inclusion criteria (elevated NTproBNP and HF hospitalization) and limited data to collect to facilitate recruitment. As the primary endpoint of all-cause mortality was unbiased and physicians were allowed to change dosages of the loop diuretic, both physicians and patients were unblinded to the treatment allocation. The trial unequivocally demonstrated that torsemide had similar effectiveness compared with furosemide for mortality (26.1 vs 26.2% after 17,4 months, HR 1.02, 95% CI, 0.89 to 1.18; P-value 0.77) as well as for mortality and all-cause hospitalizations (HR 0.92, 95% CI, 0.83 to 1.02; P-value 0.11).

The investigators should be congratulated on successfully performing the largest diuretic trial ever performed to date in ambulatory patients (N=2,859) designed to answer an important and clinically very relevant question. The pragmatic design allowed to recruit a diverse patient population (>1/3 women, >1/3 black adults, HFpEF and HFrEF). Loop diuretics are the only drug with a class I recommendation independent of LVEF to treat signs and symptoms of congestion but decisive evidence regarding diuretic agents, administration schedules, and routes of administration is limited. The recently published ADVOR (Acetazolamide in Acute Decompensated Heart Failure with Volume Overload) trial clearly demonstrated that the addition of acetazolamide to loop diuretic therapy in patients with ADHF resulted in a greater incidence of successful decongestion. Unfortunately, the pragmatic design of TRANSFORM-HF did not allow to collect data on the prevalence of decongestion which is important as NTproBNP levels were almost 4000 pg/ml at inclusion. As the authors acknowledged, insights on diuretic dosing or other guideline-directed medical therapy (GDMT) in the TRANSFORM-HF trial might have led to a different result.