Five Recent Trials That Are Changing Cardiology Practice Across the World *

Abstract

There are several recent trials that are burgeoning at a rapid pace in the field of cardiology. We picked up 5 trials that impacted our practice: CLEAR OUTCOMES trial, REVIVED BCIS2 trial, DELIVER trial, ADVOR trial, and EBC MAIN trial. After a brief description of the results of these trials, we gave our perspective of their impact on our practice.

There are several recent advances that are burgeoning at a rapid pace in the field of cardiology. Just reading the trial results may not give complete perspective about the trials. Here is a short review of 5 important trials that have been published in the recent times with our perspective of the same.

Clear Outcomes Trial (March 2023)

Statins are still clearly the best medications for Low Density Lipoprotein (LDL) control. They offer a significant cardiovascular risk reduction as proved by several randomized controlled trials. But some people do not reach the goal LDL with statin therapy and others do not tolerate statins at all. This population of statin-intolerant people and those in whom LDL cannot be controlled to the goal levels represents an unmet need.

The present alternatives or potential additions to statins in these populations are Ezetimibe, PCSK9 inhibitors, bempedoic acid, and inclisiran. Each of these agents should first be shown to reduce LDL significantly and then should be proved to mitigate cardiovascular risk directly to be included in clinical armamentarium with confidence.

Ezetimibe has shown to modestly reduce the cardiovascular event rates in the IMPROVE-IT trial. Evolocumab and alirocumab also reduce the cardiovascular event in the FOURIER and ODYSSEY OUTCOMES trials, respectively. The CLEAR OUTCOMES trial came on the heels of these trials to demonstrate that bempedoic acid can safely reduce the cardiovascular outcomes. Two points should be remembered however. The IMPROVE IT, FOURIER, and ODYSSEY OUTCOMES studies were done in those who were already using statins but could not reach the LDL goals but CLEAR OUTCOMES trial was done in those with statin-intolerance. The previous trials compared the combination of ezetimibe or PCSK9 inhibitors with the statins as against a monotherapy of statins for LDL reduction, while CLEAR OUTCOMES trial compared bempedoic acid with placebo. ORION 4 trial result using inclisiran has not published yet.

Study Population

A total of 13,970 patients unable or unwilling to take statins and either had a preexisting coronary artery disease or at a high risk of having coronary artery disease (CAD) were randomized to bempedoic acid (6,992 patients) or placebo (6,978 patients). The mean LDL was 139 mg/dL in both the groups. The mean follow-up was for 40.6 months. The primary end point was a 4-component composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.

Results

The 4-component MACE was significantly lower with bempedoic acid compared to placebo (11.7% vs 13.3%; hazard ratio: 0.87, 95% confidence interval [CI] 0.79-0.96; P = .004).

The 3-point MACE was also significantly less with bempedoic acid (8.2% vs 9.5%, P = .006). Fatal and nonfatal myocardial infarction also is less with bempedoic acid (6.2% vs 7.6%, P = .001). However, bempedoic acid had no significant effect on fatal or nonfatal stroke, death from cardiovascular causes, or death from any cause.

It should be noted that none of the cholesterol-lowering therapies which act as supplement to or substitute to statins have shown to reduce death. Bempedoic acid joins these medications. However, for those individuals who cannot tolerate statins and with CAD or at a high risk of having CAD, bempedoic acid is a reasonably safe alternative. The trial showed that bempedoic acid does not cause muscle cramps. However, the incidence of gout and cholelithiasis is higher with bempedoic acid. LDL levels have reduced in the study population by 29.2 mg/dL. While reducing the primary end point, bempedoic acid also reduced high sensitivity C-reactive protein levels by 21.6%. ¹

REVIVED BCIS2 Trial (October 2022)

Patients with ischemic cardiomyopathy are usually checked for their coronary obstructions with coronary angiography. If there are significant lesions, viability testing will be done by various means like cardiac magnetic resonance imaging, radioisotope scanning, or positron emission tomography. If the myocardium is deemed viable, the revascularization strategy is planned. Whether revascularization helps these patients or not was first assessed in the (Surgical Treatment for Ischemic Heart Failure (STICH) trial.

The incidence of death from any cause at 5 years in the STICH trial was similar in both coronary artery bypass grafting (CABG) and the medical management groups. However, patients who underwent CABG were more likely to be alive at 10 years. During the first 5 years, the early mortality of CABG offset benefits the revascularization that may have on the outcome. This led to the belief that if the procedural-related mortality can be reduced, this may translate into better outcomes even in the first 5 years. Percutaneous coronary intervention appeared ideally suited for this situation. PCI wouldn’t have an early high mortality, yet may improve outcomes while improving the blood supply to hibernating myocardium.

But like any hypothesis in medicine, this premise was to be validated and REVIVED BCIS tried to do exactly the same. A total of 700 patients with a left ventricular ejection fraction of less than 35%, extensive CAD amenable to PCI, and demonstrable viability were randomized to either PCI plus optimal medical therapy or optimal medical therapy alone. The primary end point was death from any cause or hospitalization for heart failure. Over median follow-up of 41 months, the primary end point occurred in 37.2% of the PCI group and 38% in the optimal medical therapy group (P = .96). There was no significant difference in the mean ejection fraction of the 2 groups both at 6 months and at 1 year. The quality-of-life scores were better with PCI at 6 and 12 months, but not better at 24 months. Thus, the results did not show any benefit of PCI in patients with low-ejection fraction and significant CAD even when there was a demonstrable viability.

Though this trial gives a resounding no as an answer to the question of whether revascularization with PCI helps those with ischemic cardiomyopathy, a lot of questions remain. First of all, all interventional cardiologists can recall at least some patients of ischemic cardiomyopathy who had their ejection fraction improved with PCI. Whether these patients can be distinguished from those in whom PCI will not help in improving the outcomes is not clear. Second, the STICH trial showed benefit of CABG only after 5 years from randomization. If the results could have been different after a longer follow-up is yet to be seen. Third, the revascularization index achieved in the PCI group was 71% in this trial, rising a question whether a more complete revascularization may have tilted the balance in favor of PCI. Fourth, the patients in STICH trial are roughly a decade younger than those in REVIVED-BCIS trial. Whether this has contributed to the difference in outcomes in these 2 trials is not yet apparent. Finally, unplanned revascularization was significantly higher in the optimal medical therapy group, the significance of which in the face of no mortality difference is puzzling. ²

DELIVER Trial (September 2022)

Ever since the Heart Failure with Preserved Ejection Fraction (HFrEF) is recognized as a clinical entity with reduced survival, attempts were on to find medications that reduced mortality in these patients. It has been both a frustrating and humbling experience however. While more and more medications are being discovered which reduced the mortality in patients with Heart Failure with reduced Ejection Fraction (HFrEF), the same success couldn’t be reproduced in patients with HFpEF. Trials of candesartan, spironolactone, and sacubitril–valsartan reported effects on cardiovascular death and hospitalizations for heart failure that were modest in size and were predominantly seen in those with an ejection fraction of 40-49%.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death in patients with HFrEF. This reduction in hard-end points happened both with empagliflozin as well as dapagliflozin. The same agents were then tried in HFpEF. The EMPEROR Preserved trail showed that empagliflozin is beneficial in reducing a combined end point of cardiovascular death or hospitalization for heart failure compared to placebo in those with an ejection fraction above 40%. The end point (13.8% vs 17.1% hazard ratio: 0.79; 95% CI: 0.69-0.90; P < .001) is primarily driven by a 29% reduction in hospitalizations. The deaths from cardiovascular causes or other causes did not significantly differ between the 2 groups.

The DELIVER trial came with the premise that dapagliflozin could help the patients with HFpEF. A total of 6,263 patients with heart failure with left ventricular ejection fraction above 40% were randomized to dapagliflozin 10 mg or placebo. The primary outcome of worsening heart failure or cardiovascular death was significantly lower with dapagliflozin compared with placebo (16.4% vs 19.5%; hazard ratio 0.82; 95% CI: 0.73-0.92; P < .001). Cardiovascular death occurred in 7.4% of the dapagliflozin group and 8.3% of the placebo group (hazard ration 0.88; 95% CI: 0.74-1.05). These findings are similar to those found in EMPEROR preserved trial with both trials not showing significant reduction in mortality as an independent end point. As the mortality in these patients with HFpEF is less than those with HFrEF, both the trials could be underpowered to detect a mortality benefit. But the trials differ in that the dapagliflozin showed preserved benefit for even those patients of HFpEF with an ejection fraction of above 60%, whereas there was a loss of benefit in this population with empagliflozin. The benefit was seen both in patients with diabetes and without diabetes and also those with heart failure with recovered ejection fraction.

Thus, the SGLT2 inhibitors have cemented their role in the treatment of HFpEF patients. Future trials with more patients and a longer follow-up are needed to truly assess whether these agents decrease mortality in this difficult to treat group of heart failure. ³

ADVOR Trial (September 2022)

Acute decompensated heart failure (ADHF) is a serious condition with a high mortality and needs repeated admissions and treatment. The treatment of ADHF is expensive and is a big burden for a lot of patients. The duration of treatment is a very important factor in determining the cost of managing these patients. But if discharged early without complete decongestion, these patients would carry a higher risk of readmission. That’s why these patients of ADHF need agents that can quickly, completely, and safely decongest them. For some of these patients, loop diuretics alone are not enough.

ADVOR trial tested the efficacy of intravenous acetazolamide for successful decongestion in patients with ADHF. It is a multicenter, double-blind, randomized trial. It randomized 519 patients to either intravenous (IV) acetazolamide or to placebo. The primary endpoint was successful decongestion defined as the absence of signs of volume overload within 3 days of randomization and without escalation of decongestive therapy. Volume overload is assessed by edema, pleural effusion, or ascites. Successful decongestion in ADVOR trial occurred more significantly in the acetazolamide group than in the placebo group (42.2% vs 30.5%; hazard ratio: 1.46, 95% CI 1.17-1.82; P < .001). Death or hospitalization occurred in 29.7% in the acetazolamide group and 27.8% in the placebo group. Worsening kidney function, hypokalemia, and hypotension were similar in the 2 groups. The duration of index hospitalization was a mean of 8.8 days in the acetazolamide group and 9.9 days in the placebo group.

The shorter duration of treatment for the ADHF hospitalization in turn reduces the cost of the treatment and the completeness of congestion may reduce readmissions. Thus, ADVOR trial showed benefit of IV acetazolamide in patients with ADHF. This trial excluded patients on SGLT 2 inhibitors which have now become a part of standard treatment protocol in heart failure, thus may require further study to show the benefit of acetazolamide in a contemporary medical practice. Intravenous preparation of acetazolamide at present is not widely available in India. ⁴

EBC MAIN Trial (May 2021)

The European interventional cardiologists led by the French operators have always championed the cause of a provisional bifurcation strategy as against an upfront dual stent strategy. But DKCRUSH-V trial demonstrated that a dual stent strategy was better in reducing the cardiac events (target vessel revascularization or target lesion failure) than a provisional stenting approach in the left main bifurcations. EBC MAIN trial addressed the same issue in a European set of patients. It has to be remembered that this trial did not compare the outcomes between a single stent implantation vs a double stent implantation. It compared a dedicated upfront 2-stent strategy and a stepwise layered provisional strategy. The question answered is whether deciding the strategy as 2-stent implantations before starting the procedure is better than deciding the strategy during the procedure.

The study population consisted of 467 patients with true left main bifurcation lesions (Medina type 1,1,1 or 0,1,1); both branches have to be more than 2.75 mm and each should be more than 50% narrowed. Both the provisional and dual stent strategies were clearly defined. Onyx stents were used. Most patients were treated through a transradial 6F guiding catheter. A total of 22% of the provisional strategy had a second bifurcation stent implanted. The most commonly used technique for these patients was culotte followed by T- or Tap technique. The systematic dual stent strategy also utilized culotte as the primary stenting technique.

The primary endpoint was a composite of death, myocardial infarction, and target lesion revascularization at 12 months. It occurred in 14.7% of stepwise approach vs 17.7% of the systematic dual stent group (hazard ratio: 0.8, 95% CI 0.5-1.3; P = .34). Death, myocardial infarction, target vessel revascularization, and stent thrombosis were not significantly different between the 2 groups. The procedure time, radiation exposure, and hardware used were less in the provisional group. EBC MAIN trial results clearly favored a provisional stenting strategy even for the unprotected left main lesions. But these results are diametrically opposite to those of the DKCRUSH-V trial. The authors of EBC MAIN trial tried to address the issue and suggested that the DKCRUSH operators may have been biased as the target vessel revascularizations were based on routine angiography at 1 year rather than the symptoms. They further pointed out that the lesion complexity and side branch lesion length were both higher in DKCRUSH-V trial resulting in 45% of the provisional stenting group receiving a second stent. The technique for the dedicated bifurcation strategy also differed between the 2 groups with culotte being preferred in the European trial over the DKCRUSH technique.

Finally, while the technical issue of the left main bifurcation stenting strategy remains unresolved, it should be remembered that CABG is still the preferred revascularization strategy for these patients. ⁵