Interpreting the VEST Trial: Are We Missing the Point?

At the American College of Cardiology’s 67th Annual Scientific Session held earlier this year, Dr. Jeffrey Olgin presented the results of the Vest Prevention of Early Sudden Death Trial (VEST) at the Late-Breaking Clinical Trial session.¹ The trial was a randomized, prospective, multicenter trial examining the potential benefit of using the Wearable Cardioverter Defibrillator (WCD) in patients who were immediately post myocardial infarction (MI) with a depressed left ventricular ejection fraction (LVEF) ≤35%. Patients were randomized to either the WCD with guideline-directed medical therapy (GDMT) vs GDMT alone, in a 2:1 fashion. The primary outcome of the study was sudden death (SD) and death due to ventricular arrhythmias. A pre-defined secondary endpoint was total mortality

Since the results were presented, prior to publication of the manuscript, the findings have led to mixed reactions in the cardiology community. Most of the criticism is regarding the trial missing the pre-specified primary endpoint of reduction in the rate of SD during the first 90 days after MI. However, simply coming to the conclusion that the trial was negative and thus discounting the potential benefit of the WCD is problematic and might be missing the point.

The VEST Trial Results

The VEST trial enrolled 2302 patients, making it the largest randomized trial regarding use of the WCD. Over a mean follow-up of 84 days, the rate of SD was 1.6% in the group receiving the WCD, vs 2.4% treated with GDMT alone (P=0.18). While the result was not statistically significant, the trend was positive, with a 33% relative reduction in sudden death. However, the total mortality was 3.1% in the treatment group vs 4.9% in the control group (P=0.04). Thus, there was a 36% relative risk reduction in total mortality that did reach statistical significance.¹

There are many potential contributing factors for this seemingly contradictory result. Though it is possible that patients receiving the WCD received better care or closer follow-up, potentially influencing total mortality and not the SD rate, there was not a significant difference in GDMT therapy between the two groups. There was a statistical difference in the rate of death related to stroke, with no stroke deaths seen in the study group versus 4 deaths (0.5%) in the control group.  However, the study was not powered to study a difference in stroke rate and there are statistical traps in comparing event rates between two groups where one group has a zero incidence of an event.

Interestingly, the reduction of SD represented the majority of total mortality reduction in the trial. Fourteen of the 20 patients receiving an appropriate shock survived to the 90 days. This suggests that with current treatment for MI, mechanical complications such as pump failure or rupture post-MI (conditions not treated by the WCD) did not “wash out” a total mortality benefit, as compared to our classical post-MI ICD trials.^2,3

This difference between the SD rates and total mortality rates could be explained by several other factors. Compliance in the VEST trial appears to be lower than what we see in clinical practice, and lower than what has been observed in previously reported WCD registry data. In WEARIT-II, a prospective registry of 2000 patients, there was a median compliance rate of 22.5 hours/day. This is very similar to the compliance seen in patients who chose to wear the WCD in the VEST trial.⁴ In the WCD treatment group, 80% of patients wore the device as directed at the start of the study (median of 22.4 hours/day), but this declined to 45% by the end of trial (21 hours/day). Thus, despite accurately projecting event rates for study population, this non-compliance would result in a decreased power for detecting a difference in SD. In fact, of the 25 patients who were adjudicated as having had SD in the treatment group, only 8 were wearing the WCD at the time of their death. Of the 8 patients, 5 had recurrent ventricular arrhythmia suggestive of ongoing ischemia and 3 suffered asystole or pulseless electrical activity, and thus could not be treated.

In addition, correctly adjudicating SD is difficult without detailed medical records or witnessed accounts without the use of device data. The investigators went to great lengths to eliminate any potential bias and thus the independent reviewers were blinded to any device data. Five percent of all deaths in the trial were classified as indeterminate.

Seventy patients aborted therapy by using the response buttons, which potentially dilutes the primary outcome of treatment of ventricular arrhythmia. This finding is an important consideration, given that we compare the WCD data and event rates in this population to classical primary prevention ICD trials, trials which included treated events that may not have resulted in SCD.

VEST in Context

Randomized clinical trials are the cornerstone of our practice of evidence-based medicine. The VEST trial did not meet its primary endpoint; however, the Kaplan–Meier curve for SD mortality separates early and continues to separate to 90 days, showing a positive trend. We can’t overlook the fact that in this large, randomized prospective trial, there was a significant reduction in total mortality. 

The discussion regarding whether or not the WCD should be utilized is very similar to the debate surrounding primary prevention ICD therapy.  We knew from MADIT⁵ that patients with ischemic cardiomyopathy and additional risk factors such as nonsustained ventricular tachycardia (NSVT) and programmed stimulation arrhythmia inducibility benefit from ICD implantation. This data was similar to the MUSTT trial⁶, yet in the MUSTT registry, there was still a significant risk of SCD in the electrophysiology studies (EPS)-negative group.⁷ This of course resulted in the MADIT II trial, a larger trial looking simply at left ventricular ejection fraction (LVEF) in the ischemic cardiomyopathy population.⁸ Similarly, we knew that patients with non-ischemic cardiomyopathy were at risk for sudden cardiac death.  Thus, the DEFINITE trial was designed with a primary endpoint of total mortality.⁹  The trial showed a clear trend toward improved survival, but did not reach statistical significance. It did, however, show a significant decrease in arrhythmic death. It wasn’t until the SCD-HeFT trial¹⁰ was published before a primary prevention indication for non-ischemic cardiomyopathy was established. These trials were designed to prove risk and efficacy of therapy which we already understood to be true through real-world clinical practice. The same point can be made about the efficacy of WCD therapy for patients at risk of SCD while awaiting long-term therapy. One can certainly appreciate that if the pre-defined primary endpoint of the VEST trial was total mortality (like primary prevention ICD trials), we might be looking at this trial differently.

It is well established that the patients who are post MI with a depressed LVEF are at significant risk for SCD.¹¹ Given the possibility of improvement in LVEF post revascularization or with GDMT, it is reasonable that the WCD should provide protection during this vulnerable period in which permanent ICD implantation is not indicated.

Conclusions

The VEST trial is the largest randomized, controlled trial examining the use of the WCD and clearly adds to the body of literature regarding the risk of SCD in patients post MI with a low LVEF. The trial demonstrates a significant mortality rate of 5% in this patient population. The VEST trial demonstrates a significant mortality benefit in this group of high-risk patients. It stands to reason that the benefit on arrhythmic mortality is only seen if the patients use the device. Finally, it is the obligation of physicians and other caregivers to employ a shared decision-making approach regarding the use of potentially life-saving therapies such as the WCD.

References

1. Olgin J, on behalf of VEST Investigators.  Vest Prevention of Early Sudden Death Trial (VEST).  American College of Cardiology Late Breaking Clinical Trials 2018; Orlando, Florida.
2. Hohnloser SH, Kuck KH, Dorian P, et al. Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. N Engl J Med. 2004; 351: 2481-2488.
3. Steinbeck G, Andresen D, Seidl K, et al. Defibrillator implantation early after myocardial infarction. N Engl J Med. 2009; 361: 1427-1436.
4. Kutyifa V, Moss AJ, Klein H, et al. Use of the wearable cardioverter defibrillator in high-risk cardiac patients: data from the Prospective Registry of Patients Using the Wearable Cardioverter Defibrillator (WEARIT-II Registry). Circulation. 2015; 132(17): 1613-1619.
5. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med. 1996; 335: 1933-1940.
6. Lee KL, Hafley G, Fisher JD, et al. Effect of implantable defibrillators on arrhythmic events and mortality in the multicenter unsustained tachycardia trial. Circulation. 2002; 106(2): 233-238.
7. Pires LA, Lehmann MH, Buxton AE, et.al. Differences in inducibility and prognosis of in-hospital versus out-of-hospital identified nonsustained ventricular tachycardia in patients with coronary artery disease: clinical and trial design implications. J Am Coll Cardiol. 2001 Oct; 38(4): 1156-1162.
8. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002; 346: 877-883.
9. Kadish A, Dyer A, Daubert JP, et al. Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) investigators. N Engl J Med. 2004; 350(21): 2151-2158.
10. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005; 352: 225-237.
11. Solomon SD, Zelenkofske S, McMurray JJ et al. Sudden death in patients with myocardial infarction and left ventricular dysfunction, heart failure, or both. N Engl J Med. 2005; 352(25): 2581-2588.

Disclosures: Dr. Rahul Doshi reports no conflicts of interest regarding the content herein.

Dr. Rahul Doshi can be contacted at Rahul.Doshi@med.usc.edu.