The Barostim therapy device is an active implantable device which delivers electrical stimulation to the baroreceptors located on the carotid artery with the aim of lowering blood pressure in patients with resistant hypertension. This device for baroreflex activation therapy has been produced as a first generation system (Rheos system), and the currently available second generation system (Barostim Neo). The main difference between the two systems is that for the first generation system the electrical stimulation is applied via bilateral electrodes on the external surface of the carotid arteries, while for the second generation system this was done unilaterally.
Barostim Neo is currently the only commercially available baroreflex activation therapy delivery system.
As per the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) guidelines for arterial hypertension, hypertension is defined as resistant to treatment when a therapeutic strategy that includes appropriate lifestyle measures plus a diuretic and two other antihypertensive drugs belonging to different classes at adequate doses fails to lower systolic-and diastolic blood pressure values to 140 and 90 mmHg, respectively.
The reported incidence of resistant hypertension varies from approximately 2% to 16% of a population with hypertension. Factors shown to influence the results includes white-coat effect (the elevation of blood pressure during the clinic visit in comparison with the patients’ blood pressure at home), poor medication adherence and whether office or ambulatory measurements are used.
This single technology assessment was commissioned by the The National System for Managed Introduction of New Health Technologies within the Specialist Health Service in Norway. They wanted Norwegian Institute of Public Health to evaluate the efficacy, safety and health economic documentation for use of baroreflex activation therapy in patients with drug-resistant hypertension. We have evaluated the submitted documentation against available published documentation.
Efficacy and safety
We have evaluated the submitted PICO (Population, Intervention, Comparator and Outcomes), and performed our own systematic literature search. Two review authors identified literature, performed data extraction, and assessed the included trials for risk of bias and the overall quality of evidence for each endpoint using GRADE (Grading of Recommendations Assessment, Development, and Evaluation). Finally, we critically appraised the same points in the documentation submitted by the manufacturer.
Health economic methods
In the evaluation of the submitted cost-effectiveness analysis and analysis of the budget impact from CVRx, Inc. we evaluated the submitted input data used to the cost-effectiveness model, the structure of the model and the calculations of the budget impact.
Evaluation of the documentation
Efficacy and safety
Most of the documentation, included the only randomized controlled trial, was from trials with the Rheos device. This bilateral delivery system is now unavailable.
We evaluated four multicenter trials, two for Rheos and two for Neo, including 448 patients (367 for Rheos and 81 for Neo) above 18 years with resistant hypertension.
The Rheos trials: A randomized controlled trial (The Rheos Pivotal Trial) (n=265 randomized), and the DEBuT-HT (Device Based Therapy in Hypertension Trial) with single-arm/”before and after” design (n=45). Both had published abstracts (n=322 and 18 respectively) with follow-up evidence up to six years again in a single-arm design.
The Neo trials: The Barostim Neo trial (n=30), and Wallbach 2016 (n=51), both single-arm//”before and after” design, both with 6 months follow-up.
Comparison of the efficacy and safety for the Rheos system versus the Neo system: One abstract describes a comparison of a cohort from a Neo trial with two matched cohorts from the Rheos pivotal trial.
The efficacy endpoints were changes in systolic-and diastolic blood pressure, heart rate and left ventricular mass index, and proportion of responders, either compared to a control group, or compared to a baseline value. Complications were procedure- and/or device-related serious adverse events measured for the total population. Procedural safety reports serious adverse events occurring within the 30 days of implant. Serious device-related adverse events were reported between 30 days post-implant and the month 12 visit.
Health economic documentation
The submitter performed a cost-effectiveness analysis for evaluating the cost-effectiveness of Baroreflex activation therapy for drug-resistant hypertension. They considered varation in outcomes and costs according to which treatment strategy a drug-resistant hypertension patient undergoes. A Markov cohort model was used to estimate the cost-effectiveness of the new technology compared to current practice, optimal medical therapy strategy, over a 60- year time horizon, for patients aged 54. The submitted model considered all patients who entered the Markov process, and covered the most important end-stage organ damage including myocardial infarction, stroke and transient ischemic attack, heart failure and end-stage renal disease.
In addition to presenting the results calculated by the sponsor, we performed three scenario analyses in which we adjusted various model parameters reflecting efficacy and health-related quality of life (utility values)in order to examine the effect of different assumptions on model outcomes.
We examined uncertainty in model parameters by performing one-way sensitivity analyses and presented the results as tornado diagrams.
We have evaluated the evidence for the endpoints from the randomized controlled trial to have low risk of bias and moderate quality as assessed by GRADE. We evaluated the evidence for all endpoints from the publications with single-arm designs to have high risk of bias and very low quality, hence we have very little confidence in these results. This includes all the evidence from the Neo trials.
The randomized controlled trial failed to demonstrate statistically significant differences between the Rheos activated- and Rheos inactivated therapy (sham) between baseline and 6 months for the two predefined endpoints: 1) The mean decrease in systolic blood pressure in the intervention group was 7 mm Hg larger than in the control group (14.5 larger to 0.5 smaller). 2) The proportions of patients that achieved at least a 10 mm Hg drop in office systolic blood pressure from baseline to 6 months, were 54% versus 46% (p=0.97) in the intervention and the control group, respectively.
The evidence was influenced of when (pre-or post-implant) and how (office and ambulatory) blood pressure is measured.
The Rheos system had an event-free rate of serious adverse events, compared to pre-specified objective performance criteria based on similar implantable devices, that was comparable (p=1.00) for procedural safety, and higher (p<0.001) for device- related safety. From the Neo trials there is too little evidence to conclude for safety (only 30 and 51 patients respectively in the two main trials). However, one may think that the safety for the unilateral device could be in the same order as the bilateral device. Long-term safety data beyond 12 months are missing.
Health economic results
The calculated incremental cost-effectivness ratio (ICER) based on the submitted economic model over a 60-year time horizon was NOK 509,016 per quality adjusted life year (QALY) gained for patients aged 54. We varied clinical effectiveness values for the reduction of systolic blood pressure in both treatment arms in order to test a different interpretation of trial results. In our first scenario, we captured changes in blood pressure based on the post-implant baseline measurement of office systolic blood pressure, measured at 6 months from the Rheos trial. The calculated ICER for this scenario analysis rose to NOK 796,761 per QALY gained. In a second scenario analysis we adjusted both the clinical effectiveness values (as in scenario 1) and the utility value related to the hypertensive state. The resulting ICER increased to NOK 896,898 per QALY gained. We also performed a third scenario analysis based on the post hoc analysis found in the Rheos trial, using pre-implant baseline measurements for the clinical effectiveness, and the adjusted utility value related to the hypertensive state (as in scenario 2). The calculated ICER increased to NOK 856,312 per QALY gained. All the scenario analyses showed a less cost-effective result than presented in the submission.
One-way sensitivity analysis showed that the results were most sensitive to changes in the age of the patient population, the costs related to the Barostim therapy (battery, system and replacement), and the 6-month probability of hypertensive crisis in the optimal medical therapy arm. The patient’s age had the largest uncertainty and the ICER varied between NOK 517,286 and NOK 2,192,157.
The submitter estimated that the total added costs of implementing Barostim Neo system in Norway would be about NOK 24,000,000 for the first five years. Due to uncertainties associated with the yearly costs used in the calculation of budget impact by the submitter, we re-calculated the additional costs of introducing the technology in Norway. The results of our budget impact analysis showed that assuming 20 new patients each year, the total added expected cost would be about NOK 24,500,000 for the first five years after adoption of Barostim Neo system in Norway. The cost of battery replacement (approximately half the cost of initial device and implantation) becomes relevant after six years.
We have performed a single technology assessment of the use of Baroreflex activation therapy for drug-resistant hypertension. The submission came from CVRx, Inc. Our conclusion is that we disagree with the submitter’s conclusion regarding efficacy and therefore also cost-effectiveness.
Efficacy and safety
Both the submitter and we have evaluated the same main trials and extracted the same main evidence from these. The reason for our disagreement lays in the analyses and the evaluation of the evidence.
The submitter chose to conclude (claim) from a pooled analysis based on evidence from trials with no control group, and not from available evidence with relative effect estimates from the randomized controlled part of the Rheos pivotal trial. The use of the evidence from the pooled analysis from trials with no control group, results in an overestimate of the efficacy evidence, with a following positive impact on the cost- effectiveness analysis.
Factors that influence on the results
We have observed that office measurements give greater changes from baseline in systolic- and diastolic blood pressures than ambulatory measurements. Further, from the randomized controlled trial we observed that the use of pre-implant measurements as baseline values for systolic blood pressure gave larger reduction at 6 months, than if the baseline values were measured post-implant.
We believe a randomized controlled trial is needed. This is also suggested from our sister organizations in the United Kingdom and Canada (NICE and CADTH respectively). We suggest that the optimal study design would be a randomized controlled trial, with sufficient number of patients, comparing active Barostim Neo device with the best available pharmacological treatment using ambulatory measurements of blood pressure and pre-implant measurements as baseline. If the control group is a sham control (or if one want this as a third arm), it could possibly be necessary or interesting to use post-implant measurements in addition to pre-implant measurements. The follow-up should be at least one year.
The submitter performed an economic evaluation by developing a decision tree combined with a Markov model. The model included all patients who entered the Markov process, and covered the most important end-stage organ damage including myocardial infarction, stroke and transient ischemic attack (TIA), heart failure and end-stage renal disease.
Based on thorough review and input given by the clinical experts, we think that the health economic model captured the outcomes that are clinically relevant for the defined population and intervention.
However, there were some uncertain points to consider regarding the submission. We performed three scenario analyses, one scenario analysis where we revised only the clinical effectiveness values related to the reduction in systolic blood pressure and two scenario analyses where we revised and corrected both the clinical effectiveness values and the utility value related to the hypertensive state. In all scenario analyses the new technology combined with optimal treatment care became less cost-effective than the submitted cost-effectivness results.
Further, we investigated the impact of reducing the 60-year time horizon, which seemed too long for a population with an average age of 54, to a time horizon of 40-years. The shorter time horizon had little effect on the results. Finally, we adjusted the shares and dosages of the pharmaceutical in both model arms to reflect actual practice in Norway. These adjustments had little impact on the results.
Efficacy and safety
Our data extraction from the available literature cannot support the claims from the submitter.
We found that there is insufficient evidence to demonstrate efficacy for both the Rheos system and the Barostim Neo™ system.
The safety for the Rheos system had an event-free rate, compared to pre-specified objective performance criteria based on similar implantable devices, that was comparable (p=1.00) for serious procedural safety, and higher (p<0.001) for serious device-related safety. One may think that the safety for the unilateral device could be in the same order as the bilateral device. Long-term safety data beyond 12 months are missing.
Based on ICER levels that have typically been considered cost-effective in Norway, the submitted economic analysis indicates that Barostim therapy could be cost-effective in patients with drug-resistant hypertension. However, after adjusting the model to account for important shortcomings in the submitted analysis, related to clinical effect and health-related quality of life, the ICER rises well above the level that has been considered cost-effective in Norway.
Scenario analyses indicate that the results are particularly sensitive to patient age and cost of the Barostim device (battery, system and replacement). Treatment could be cost-effective among a young population group or with a decrease in Barostim costs.