Hani Jneid, MD, FACC, FAHA, FSCAI

Bicuspid aortic valve is the most common congenital cardiac abnormality in humans and is a significant risk factor for premature aortic valve dysfunction due to accelerated leaflet deterioration and calcification from altered hemodynamics. From 20% to 50% of patients with bicuspid aortic valve need aortic valve replacement during their lifetime, mostly for aortic stenosis.^1,2

See related article

While 0.5% to 2% of the general population are born with a bicuspid aortic valve, more than 40% of patients (mainly younger patients) who undergo surgical or transcatheter intervention for aortic valve disease in some cohorts have this abnormality, suggesting that its true prevalence may be underreported.³

In the past decade, transcatheter aortic valve replacement (TAVR) has cemented its place as an option for patients with severe tricuspid aortic stenosis who cannot undergo surgery because their surgical risk is intermediate or high.⁴ However, most of the studies of balloon-expandable and self-expanding TAVR devices have excluded patients with bicuspid aortic valve.

BICUSPID AORTIC VALVE POSES CHALLENGES FOR TAVR

As TAVR is explored in younger and lower-risk populations, in which the prevalence of bicuspid aortic valve is presumably higher, the discussion of feasibility, safety, and efficacy of TAVR in patients with bicuspid aortic valve is both important and timely.

Bicuspid aortic valve is commonly categorized according to the Sievers classification,⁵ which describes 3 main morphologic types (designated types 0, 1, and 2) according to the number of raphes connecting the leaflets. Unique anatomic features of bicuspid aortic valve render the TAVR procedure challenging in these patients and merit consideration. These include, but are not limited to:

• Asymmetric calcification of the valve leaflets and calcified raphes. This results in asymmetric and incomplete expansion of the prosthesis, leading to incomplete sealing and paravalvular leak.
• A larger and more elliptically shaped aortic annulus, leading to challenges with proper sizing and apposition of the prosthesis
• Concomitant aortopathy, posing a higher risk of aortic rupture, dissection, paravalvular leak, and other complications during implantation.

Thus, compared with patients with tricuspid degenerative aortic stenosis, patients undergoing TAVR who have bicuspid aortic valve have a higher short-term risk of death and a higher risk of residual aortic regurgitation, and are more likely to need implantation of a second valve.

PARAVALVULAR LEAK

Paravalvular leak, arguably an independent marker of higher morbidity and mortality risk after TAVR, is more common in patients with bicuspid aortic valve undergoing TAVR than in those with tricuspid aortic valve. Earlier studies reported rates of moderate or severe paravalvular leak between 16% and 32%.^6,7

The newer-generation balloon-expandable Sapien 3 valve (Edwards Lifesciences, Irvine, CA) is associated with a lower incidence of moderate or severe paravalvular leak than earlier devices, mainly attributable to its outer skirt, which allows more complete sealing.⁸ There are also reports of successful treatment of bicuspid aortic valve stenosis using the Lotus device (Boston Scientific, Marlborough, MA).⁹ This device features adaptive sealing along with retrievability and repositioning ability, which may facilitate optimal positioning and prevent paravalvular leak.

Sizing of the prosthesis in patients with bicuspid aortic valve stenosis remains a challenge: some experts advocate the usual practice of measuring the perimeter and area at the level of the annulus, while others advocate measuring at the level of the commissures, 4 to 8 mm above the annulus. Balloon valvuloplasty may be a useful sizing tool, though it carries the hazards of severe aortic regurgitation and periprocedural stroke.

Angiography of the ascending aorta during balloon valvuloplasty can help verify whether an adequate seal is achievable and aid in selecting an appropriately sized prosthesis. Liu et al¹⁰ performed sequential balloon aortic valvuloplasty before TAVR with a self-expanding valve in 12 patients. Of these, 11 (91.7%) received a smaller device than they would have with multidetector computed tomography-guided annulus measurement.

Given that a larger valve may increase the risk of annular rupture, implantation of a smaller valve is always reasonable in bicuspid aortic valve as long as it achieves appropriate sealing with no paravalvular leak.

THE NEED FOR A PACEMAKER

After undergoing TAVR, more patients who have a bicuspid aortic valve need a permanent pacemaker than those who have a tricuspid aortic valve. This group appears to be more vulnerable to conduction abnormalities after TAVR, and rates of new pacemaker implantation as high as 25% have been reported with the newer-generation devices. Perlman et al⁸ observed that even when the Sapien 3 valve was implanted high in the left ventricular outflow tract, nearly 10% of patients needed a new pacemaker.

This is an important issue, as most patients with bicuspid aortic valve with severe aortic stenosis are relatively young and may endure deleterious effects from long-term pacing.

LONG-TERM OUTCOMES

The data on long-term outcomes of patients with bicuspid aortic valve who undergo TAVR are limited, and the available studies were small, with relatively short-term follow-up. However, Yoon et al compared TAVR outcomes between bicuspid and tricuspid aortic stenosis patients using propensity-score matching and demonstrated comparable all-cause mortality rates at 2 years (17.2% vs 19.4%, P = .28).⁶

Given the relatively long life expectancy of patients with bicuspid aortic valve undergoing TAVR, who tend to be younger than those with tricuspid aortic valve stenosis, longer-term data are needed to draw meaningful conclusions about the durability of transcatheter valves in this population. The bicuspid aortic valve is asymmetric, so that during TAVR the stent may not expand completely, and this in theory may result in more strain on the prosthesis and accelerate its structural deterioration.

In a recent meta-analysis, Reddy et al¹¹ analyzed 13 observational studies in 758 patients with severe bicuspid aortic valve stenosis undergoing TAVR with older and newer devices. The mean Society of Thoracic Surgeons Predicted Risk of Mortality score, which predicts the risk of death within 30 days, was 5.0%, but the actual rate was 3.7% (95% confidence interval [CI] 2.1%–5.6%). A high procedural success rate of 95% (95% CI 90.2%–98.5%] was also noted, but the rates of new permanent pacemaker implantation (17.9%, 95% CI 14.2%–22%) and severe perivalvular leak (12.2%, 95% CI 3.1%–24.8%) were somewhat elevated.¹¹

NOT FOR ALL, BUT AN EMERGING, VIABLE OPTION

As implanted prostheses and TAVR techniques undergo continuous improvement and as the experience of operators and institutions advances, procedural outcomes will likely improve.

The available data suggest that TAVR with the newer devices, when performed by experienced hands, is a viable option across most of the risk spectrum in patients with severe tricuspid aortic stenosis, including low-risk patients,¹² and selectively in patients with bicuspid aortic valve stenosis. However, for patients with bicuspid aortic valve with severe aortic stenosis and associated aortopathy, surgery remains the standard of care.

More study is needed to identify patients with bicuspid aortic valve who can be safely and effectively treated with TAVR.

Bicuspid aortic valve is the most common congenital cardiac abnormality in humans and is a significant risk factor for premature aortic valve dysfunction due to accelerated leaflet deterioration and calcification from altered hemodynamics. From 20% to 50% of patients with bicuspid aortic valve need aortic valve replacement during their lifetime, mostly for aortic stenosis.^1,2

See related article

While 0.5% to 2% of the general population are born with a bicuspid aortic valve, more than 40% of patients (mainly younger patients) who undergo surgical or transcatheter intervention for aortic valve disease in some cohorts have this abnormality, suggesting that its true prevalence may be underreported.³

In the past decade, transcatheter aortic valve replacement (TAVR) has cemented its place as an option for patients with severe tricuspid aortic stenosis who cannot undergo surgery because their surgical risk is intermediate or high.⁴ However, most of the studies of balloon-expandable and self-expanding TAVR devices have excluded patients with bicuspid aortic valve.

BICUSPID AORTIC VALVE POSES CHALLENGES FOR TAVR

As TAVR is explored in younger and lower-risk populations, in which the prevalence of bicuspid aortic valve is presumably higher, the discussion of feasibility, safety, and efficacy of TAVR in patients with bicuspid aortic valve is both important and timely.

Bicuspid aortic valve is commonly categorized according to the Sievers classification,⁵ which describes 3 main morphologic types (designated types 0, 1, and 2) according to the number of raphes connecting the leaflets. Unique anatomic features of bicuspid aortic valve render the TAVR procedure challenging in these patients and merit consideration. These include, but are not limited to:

• Asymmetric calcification of the valve leaflets and calcified raphes. This results in asymmetric and incomplete expansion of the prosthesis, leading to incomplete sealing and paravalvular leak.
• A larger and more elliptically shaped aortic annulus, leading to challenges with proper sizing and apposition of the prosthesis
• Concomitant aortopathy, posing a higher risk of aortic rupture, dissection, paravalvular leak, and other complications during implantation.

Thus, compared with patients with tricuspid degenerative aortic stenosis, patients undergoing TAVR who have bicuspid aortic valve have a higher short-term risk of death and a higher risk of residual aortic regurgitation, and are more likely to need implantation of a second valve.

PARAVALVULAR LEAK

Paravalvular leak, arguably an independent marker of higher morbidity and mortality risk after TAVR, is more common in patients with bicuspid aortic valve undergoing TAVR than in those with tricuspid aortic valve. Earlier studies reported rates of moderate or severe paravalvular leak between 16% and 32%.^6,7

The newer-generation balloon-expandable Sapien 3 valve (Edwards Lifesciences, Irvine, CA) is associated with a lower incidence of moderate or severe paravalvular leak than earlier devices, mainly attributable to its outer skirt, which allows more complete sealing.⁸ There are also reports of successful treatment of bicuspid aortic valve stenosis using the Lotus device (Boston Scientific, Marlborough, MA).⁹ This device features adaptive sealing along with retrievability and repositioning ability, which may facilitate optimal positioning and prevent paravalvular leak.

Sizing of the prosthesis in patients with bicuspid aortic valve stenosis remains a challenge: some experts advocate the usual practice of measuring the perimeter and area at the level of the annulus, while others advocate measuring at the level of the commissures, 4 to 8 mm above the annulus. Balloon valvuloplasty may be a useful sizing tool, though it carries the hazards of severe aortic regurgitation and periprocedural stroke.

Angiography of the ascending aorta during balloon valvuloplasty can help verify whether an adequate seal is achievable and aid in selecting an appropriately sized prosthesis. Liu et al¹⁰ performed sequential balloon aortic valvuloplasty before TAVR with a self-expanding valve in 12 patients. Of these, 11 (91.7%) received a smaller device than they would have with multidetector computed tomography-guided annulus measurement.

Given that a larger valve may increase the risk of annular rupture, implantation of a smaller valve is always reasonable in bicuspid aortic valve as long as it achieves appropriate sealing with no paravalvular leak.

THE NEED FOR A PACEMAKER

After undergoing TAVR, more patients who have a bicuspid aortic valve need a permanent pacemaker than those who have a tricuspid aortic valve. This group appears to be more vulnerable to conduction abnormalities after TAVR, and rates of new pacemaker implantation as high as 25% have been reported with the newer-generation devices. Perlman et al⁸ observed that even when the Sapien 3 valve was implanted high in the left ventricular outflow tract, nearly 10% of patients needed a new pacemaker.

This is an important issue, as most patients with bicuspid aortic valve with severe aortic stenosis are relatively young and may endure deleterious effects from long-term pacing.

LONG-TERM OUTCOMES

The data on long-term outcomes of patients with bicuspid aortic valve who undergo TAVR are limited, and the available studies were small, with relatively short-term follow-up. However, Yoon et al compared TAVR outcomes between bicuspid and tricuspid aortic stenosis patients using propensity-score matching and demonstrated comparable all-cause mortality rates at 2 years (17.2% vs 19.4%, P = .28).⁶

Given the relatively long life expectancy of patients with bicuspid aortic valve undergoing TAVR, who tend to be younger than those with tricuspid aortic valve stenosis, longer-term data are needed to draw meaningful conclusions about the durability of transcatheter valves in this population. The bicuspid aortic valve is asymmetric, so that during TAVR the stent may not expand completely, and this in theory may result in more strain on the prosthesis and accelerate its structural deterioration.

In a recent meta-analysis, Reddy et al¹¹ analyzed 13 observational studies in 758 patients with severe bicuspid aortic valve stenosis undergoing TAVR with older and newer devices. The mean Society of Thoracic Surgeons Predicted Risk of Mortality score, which predicts the risk of death within 30 days, was 5.0%, but the actual rate was 3.7% (95% confidence interval [CI] 2.1%–5.6%). A high procedural success rate of 95% (95% CI 90.2%–98.5%] was also noted, but the rates of new permanent pacemaker implantation (17.9%, 95% CI 14.2%–22%) and severe perivalvular leak (12.2%, 95% CI 3.1%–24.8%) were somewhat elevated.¹¹

NOT FOR ALL, BUT AN EMERGING, VIABLE OPTION

As implanted prostheses and TAVR techniques undergo continuous improvement and as the experience of operators and institutions advances, procedural outcomes will likely improve.

The available data suggest that TAVR with the newer devices, when performed by experienced hands, is a viable option across most of the risk spectrum in patients with severe tricuspid aortic stenosis, including low-risk patients,¹² and selectively in patients with bicuspid aortic valve stenosis. However, for patients with bicuspid aortic valve with severe aortic stenosis and associated aortopathy, surgery remains the standard of care.

More study is needed to identify patients with bicuspid aortic valve who can be safely and effectively treated with TAVR.

Bicuspid aortic valve is the most common congenital cardiac abnormality in humans and is a significant risk factor for premature aortic valve dysfunction due to accelerated leaflet deterioration and calcification from altered hemodynamics. From 20% to 50% of patients with bicuspid aortic valve need aortic valve replacement during their lifetime, mostly for aortic stenosis.^1,2

See related article

While 0.5% to 2% of the general population are born with a bicuspid aortic valve, more than 40% of patients (mainly younger patients) who undergo surgical or transcatheter intervention for aortic valve disease in some cohorts have this abnormality, suggesting that its true prevalence may be underreported.³

In the past decade, transcatheter aortic valve replacement (TAVR) has cemented its place as an option for patients with severe tricuspid aortic stenosis who cannot undergo surgery because their surgical risk is intermediate or high.⁴ However, most of the studies of balloon-expandable and self-expanding TAVR devices have excluded patients with bicuspid aortic valve.

BICUSPID AORTIC VALVE POSES CHALLENGES FOR TAVR

As TAVR is explored in younger and lower-risk populations, in which the prevalence of bicuspid aortic valve is presumably higher, the discussion of feasibility, safety, and efficacy of TAVR in patients with bicuspid aortic valve is both important and timely.

Bicuspid aortic valve is commonly categorized according to the Sievers classification,⁵ which describes 3 main morphologic types (designated types 0, 1, and 2) according to the number of raphes connecting the leaflets. Unique anatomic features of bicuspid aortic valve render the TAVR procedure challenging in these patients and merit consideration. These include, but are not limited to:

• Asymmetric calcification of the valve leaflets and calcified raphes. This results in asymmetric and incomplete expansion of the prosthesis, leading to incomplete sealing and paravalvular leak.
• A larger and more elliptically shaped aortic annulus, leading to challenges with proper sizing and apposition of the prosthesis
• Concomitant aortopathy, posing a higher risk of aortic rupture, dissection, paravalvular leak, and other complications during implantation.

Thus, compared with patients with tricuspid degenerative aortic stenosis, patients undergoing TAVR who have bicuspid aortic valve have a higher short-term risk of death and a higher risk of residual aortic regurgitation, and are more likely to need implantation of a second valve.

PARAVALVULAR LEAK

Paravalvular leak, arguably an independent marker of higher morbidity and mortality risk after TAVR, is more common in patients with bicuspid aortic valve undergoing TAVR than in those with tricuspid aortic valve. Earlier studies reported rates of moderate or severe paravalvular leak between 16% and 32%.^6,7

The newer-generation balloon-expandable Sapien 3 valve (Edwards Lifesciences, Irvine, CA) is associated with a lower incidence of moderate or severe paravalvular leak than earlier devices, mainly attributable to its outer skirt, which allows more complete sealing.⁸ There are also reports of successful treatment of bicuspid aortic valve stenosis using the Lotus device (Boston Scientific, Marlborough, MA).⁹ This device features adaptive sealing along with retrievability and repositioning ability, which may facilitate optimal positioning and prevent paravalvular leak.

Sizing of the prosthesis in patients with bicuspid aortic valve stenosis remains a challenge: some experts advocate the usual practice of measuring the perimeter and area at the level of the annulus, while others advocate measuring at the level of the commissures, 4 to 8 mm above the annulus. Balloon valvuloplasty may be a useful sizing tool, though it carries the hazards of severe aortic regurgitation and periprocedural stroke.

Angiography of the ascending aorta during balloon valvuloplasty can help verify whether an adequate seal is achievable and aid in selecting an appropriately sized prosthesis. Liu et al¹⁰ performed sequential balloon aortic valvuloplasty before TAVR with a self-expanding valve in 12 patients. Of these, 11 (91.7%) received a smaller device than they would have with multidetector computed tomography-guided annulus measurement.

Given that a larger valve may increase the risk of annular rupture, implantation of a smaller valve is always reasonable in bicuspid aortic valve as long as it achieves appropriate sealing with no paravalvular leak.

THE NEED FOR A PACEMAKER

After undergoing TAVR, more patients who have a bicuspid aortic valve need a permanent pacemaker than those who have a tricuspid aortic valve. This group appears to be more vulnerable to conduction abnormalities after TAVR, and rates of new pacemaker implantation as high as 25% have been reported with the newer-generation devices. Perlman et al⁸ observed that even when the Sapien 3 valve was implanted high in the left ventricular outflow tract, nearly 10% of patients needed a new pacemaker.

This is an important issue, as most patients with bicuspid aortic valve with severe aortic stenosis are relatively young and may endure deleterious effects from long-term pacing.

LONG-TERM OUTCOMES

The data on long-term outcomes of patients with bicuspid aortic valve who undergo TAVR are limited, and the available studies were small, with relatively short-term follow-up. However, Yoon et al compared TAVR outcomes between bicuspid and tricuspid aortic stenosis patients using propensity-score matching and demonstrated comparable all-cause mortality rates at 2 years (17.2% vs 19.4%, P = .28).⁶

Given the relatively long life expectancy of patients with bicuspid aortic valve undergoing TAVR, who tend to be younger than those with tricuspid aortic valve stenosis, longer-term data are needed to draw meaningful conclusions about the durability of transcatheter valves in this population. The bicuspid aortic valve is asymmetric, so that during TAVR the stent may not expand completely, and this in theory may result in more strain on the prosthesis and accelerate its structural deterioration.

In a recent meta-analysis, Reddy et al¹¹ analyzed 13 observational studies in 758 patients with severe bicuspid aortic valve stenosis undergoing TAVR with older and newer devices. The mean Society of Thoracic Surgeons Predicted Risk of Mortality score, which predicts the risk of death within 30 days, was 5.0%, but the actual rate was 3.7% (95% confidence interval [CI] 2.1%–5.6%). A high procedural success rate of 95% (95% CI 90.2%–98.5%] was also noted, but the rates of new permanent pacemaker implantation (17.9%, 95% CI 14.2%–22%) and severe perivalvular leak (12.2%, 95% CI 3.1%–24.8%) were somewhat elevated.¹¹

NOT FOR ALL, BUT AN EMERGING, VIABLE OPTION

As implanted prostheses and TAVR techniques undergo continuous improvement and as the experience of operators and institutions advances, procedural outcomes will likely improve.

The available data suggest that TAVR with the newer devices, when performed by experienced hands, is a viable option across most of the risk spectrum in patients with severe tricuspid aortic stenosis, including low-risk patients,¹² and selectively in patients with bicuspid aortic valve stenosis. However, for patients with bicuspid aortic valve with severe aortic stenosis and associated aortopathy, surgery remains the standard of care.

More study is needed to identify patients with bicuspid aortic valve who can be safely and effectively treated with TAVR.

When renal sympathetic denervation, an endovascular procedure designed to treat resistant hypertension, failed to meet its efficacy goal in the SYMPLICITY HTN-3 trial,¹ the news was disappointing.

See related article

In this issue of the Cleveland Clinic Journal of Medicine, Shishehbor et al² provide a critical review of the findings of that trial and summarize its intricacies, as well as the results of other important trials of renal denervation therapy for hypertension. To their excellent observations, we would like to add some of our own.

HYPERTENSION: COMMON, OFTEN RESISTANT

The worldwide prevalence of hypertension is increasing. In the year 2000, about 26% of the adult world population had hypertension; by the year 2025, the number is projected to rise to 29%—1.56 billion people.³

Only about 50% of patients with hypertension are treated for it and, of those, about half have it adequately controlled. In one report, about 30% of US patients with hypertension had adequate blood pressure control.⁴

Patients who have uncontrolled hypertension are usually older and more obese, have higher baseline blood pressure and excessive salt intake, and are more likely to have chronic kidney disease, diabetes, obstructive sleep apnea, and aldosterone excess.⁵ Many of these conditions are also associated with increased sympathetic nervous system activity.⁶

Resistance and pseudoresistance

But lack of control of blood pressure is not the same as resistant hypertension. It is important to differentiate resistant hypertension from pseudoresistant hypertension, ie, hypertension that only seems to be resistant.⁷ Resistant hypertension affects 12.8% of all drug-treated hypertensive patients in the United States, according to data from the National Health and Nutrition Examination Survey.⁸

Factors that can cause pseudoresistant hypertension include:

Suboptimal antihypertensive regimens (truly resistant hypertension means blood pressure that remains high despite concurrent treatment with 3 antihypertensive drugs of different classes, 1 of which is a diuretic, in maximal doses)

The white coat effect (higher blood pressure in the office than at home, presumably due to the stress of an office visit)

• Suboptimal blood pressure measurement techniques (eg, use of a cuff that is too small, causing falsely high readings)
• Physician inertia (eg, failure to change a regimen that is not working)
• Lifestyle factors (eg, excessive sodium intake)
• Medications that interfere with blood pressure control (eg, nonsteroidal anti-inflammatory drugs)
• Poor adherence to prescribed medications.

Causes of secondary hypertension such as obstructive sleep apnea, primary aldosteronism, and renal artery stenosis should also be ruled out before concluding that a patient has resistant hypertension.

Hypertension causes a myriad of medical diseases, including accelerated atherosclerosis, myocardial ischemia and infarction, both systolic and diastolic heart failure, rhythm problems (eg, atrial fibrillation), and stroke.

Most patients with resistant hypertension have no identifiable reversible causes of it, exhibit increased sympathetic nervous system activity, and have increased risk of cardiovascular events. The risk can be reduced by treatment.^9,10

Adequate and sustained treatment of hypertension prevents and mitigates its complications. The classic Veterans Administration Cooperative Study in the 1960s demonstrated a 96% reduction in cardiovascular events over 18 months with the use of 3 antihypertensive medications in patients with severe hypertension.¹¹ A reduction of as little as 2 mm Hg in the mean blood pressure has been associated with a 10% reduction in the risk of stroke mortality and a 7% decrease in ischemic heart disease mortality.¹² This is an important consideration when evaluating the clinical end points of hypertension trials.

SYMPLICITY HTN-3 TRIAL: WHAT DID WE LEARN?

As controlling blood pressure is paramount in reducing cardiovascular complications, it is only natural to look for innovative strategies to supplement the medical treatments of hypertension.

The multicenter SYMPLICITY HTN-3 trial¹ was undertaken to establish the efficacy of renal-artery denervation using radiofrequency energy delivered by a catheter-based system (Symplicity RDN, Medtronic, Dublin, Ireland). This randomized, sham-controlled, blinded study did not show a benefit from this procedure with respect to either of its efficacy end points—at 6 months, a reduction in office systolic blood pressure of at least 5 mm Hg more than with medical therapy alone, or a reduction in mean ambulatory systolic pressure of at least 2 mm Hg more than with medical therapy alone.

Despite the negative results, this medium-size (N = 535) randomized clinical trial still represents the highest-level evidence in the field, and we ought to learn something from it.

Limitations of SYMPLICITY HTN-3

Several factors may have contributed to the negative results of the trial. 

Patient selection. For the most part, patients enrolled in renal denervation trials, including SYMPLICITY HTN-3, were not selected on the basis of heightened sympathetic nervous system activity. Assessment of sympathetic nervous system activity may identify the population most likely to achieve an adequate response.

Of note, the baseline blood pressure readings of patients in this trial were higher in the office than on ambulatory monitoring. Patients with white coat hypertension have increased sympathetic nervous system activity and thus might actually be good candidates for renal denervation therapy.

Adequacy of ablation was not measured. Many argue that an objective measure of the adequacy of the denervation procedure (qualitative or quantitative) should have been implemented and, if it had been, the results might have been different. For example, when ablation is performed in the main renal artery as well as the branches, the efficacy in reducing levels of norepinephrine is improved.¹³

Blood pressure fell in both groups. In SYMPLICITY HTN-3 and many other renal denervation trials, patients were assessed using both office and ambulatory blood pressure measurements. The primary end point was the office blood pressure measurement, with a 5-mm Hg difference in reduction chosen to define the superiority margin. This margin was chosen because even small reductions in blood pressure are known to decrease adverse events caused by hypertension. Notably, blood pressure fell significantly in both the control and intervention groups, with an intergroup difference of 2.39 mm Hg (not statistically significant) in favor of denervation.

Medication questions. The SYMPLICITY HTN-3 patients were supposed to be on stable medical regimens with maximal tolerated doses before the procedure. However, it was difficult to assess patients’ adherence to and tolerance of medical therapies. Many (about 40%) of the patients had their medications changed during the study.¹

Therefore, a critical look at the study enrollment criteria may shed more light on the reasons for the negative findings. Did these patients truly have resistant hypertension? Before they underwent the treatment, was their prestudy pharmacologic regimen adequately intensified?

After the findings of the SYMPLICITY HTN-3 study were released, several other trials—such as the Renal Denervation for Hypertension (DENERHTN)¹⁴ and Prague-15 trials¹⁵—reported conflicting results. Notably, these were not sham-controlled trials.

Newer studies with robust trial designs are ongoing. A quick search of www.clinicaltrials.gov reveals that at least 89 active clinical trials of renal denervation are registered as of the date of this writing. Excluding those with unknown status, there are 63 trials open or ongoing.

Clinical trials are also ongoing to determine the effects of renal denervation in patients with heart failure, atrial fibrillation, sleep apnea, and chronic kidney disease, all of which are known to involve heightened sympathetic nervous system activity.

NOT READY FOR CLINICAL USE

Although nonpharmacologic treatments of hypertension continue to be studied and are supported by an avalanche of trials in animals and small, mostly nonrandomized trials in humans, one should not forget that the SYMPLICITY HTN-3 trial simply did not meet its primary efficacy end points. We need definitive clinical evidence showing that renal denervation reduces either blood pressure or clinical events before it becomes a mainstream therapy in humans.

Additional trials are being conducted that were designed in accordance with the recommendations of the European Clinical Consensus Conference for Renal Denervation¹⁶ in terms of study population, design, and end points. Well-designed studies that conform to those recommendations are critical.

Finally, although our enthusiasm for renal denervation as a treatment of hypertension is tempered, there have been no noteworthy safety concerns related to the procedure, which certainly helps maintain the research momentum in this field.              

When renal sympathetic denervation, an endovascular procedure designed to treat resistant hypertension, failed to meet its efficacy goal in the SYMPLICITY HTN-3 trial,¹ the news was disappointing.

See related article

In this issue of the Cleveland Clinic Journal of Medicine, Shishehbor et al² provide a critical review of the findings of that trial and summarize its intricacies, as well as the results of other important trials of renal denervation therapy for hypertension. To their excellent observations, we would like to add some of our own.

HYPERTENSION: COMMON, OFTEN RESISTANT

The worldwide prevalence of hypertension is increasing. In the year 2000, about 26% of the adult world population had hypertension; by the year 2025, the number is projected to rise to 29%—1.56 billion people.³

Only about 50% of patients with hypertension are treated for it and, of those, about half have it adequately controlled. In one report, about 30% of US patients with hypertension had adequate blood pressure control.⁴

Patients who have uncontrolled hypertension are usually older and more obese, have higher baseline blood pressure and excessive salt intake, and are more likely to have chronic kidney disease, diabetes, obstructive sleep apnea, and aldosterone excess.⁵ Many of these conditions are also associated with increased sympathetic nervous system activity.⁶

Resistance and pseudoresistance

But lack of control of blood pressure is not the same as resistant hypertension. It is important to differentiate resistant hypertension from pseudoresistant hypertension, ie, hypertension that only seems to be resistant.⁷ Resistant hypertension affects 12.8% of all drug-treated hypertensive patients in the United States, according to data from the National Health and Nutrition Examination Survey.⁸

Factors that can cause pseudoresistant hypertension include:

Suboptimal antihypertensive regimens (truly resistant hypertension means blood pressure that remains high despite concurrent treatment with 3 antihypertensive drugs of different classes, 1 of which is a diuretic, in maximal doses)

The white coat effect (higher blood pressure in the office than at home, presumably due to the stress of an office visit)

• Suboptimal blood pressure measurement techniques (eg, use of a cuff that is too small, causing falsely high readings)
• Physician inertia (eg, failure to change a regimen that is not working)
• Lifestyle factors (eg, excessive sodium intake)
• Medications that interfere with blood pressure control (eg, nonsteroidal anti-inflammatory drugs)
• Poor adherence to prescribed medications.

Causes of secondary hypertension such as obstructive sleep apnea, primary aldosteronism, and renal artery stenosis should also be ruled out before concluding that a patient has resistant hypertension.

Hypertension causes a myriad of medical diseases, including accelerated atherosclerosis, myocardial ischemia and infarction, both systolic and diastolic heart failure, rhythm problems (eg, atrial fibrillation), and stroke.

Most patients with resistant hypertension have no identifiable reversible causes of it, exhibit increased sympathetic nervous system activity, and have increased risk of cardiovascular events. The risk can be reduced by treatment.^9,10

Adequate and sustained treatment of hypertension prevents and mitigates its complications. The classic Veterans Administration Cooperative Study in the 1960s demonstrated a 96% reduction in cardiovascular events over 18 months with the use of 3 antihypertensive medications in patients with severe hypertension.¹¹ A reduction of as little as 2 mm Hg in the mean blood pressure has been associated with a 10% reduction in the risk of stroke mortality and a 7% decrease in ischemic heart disease mortality.¹² This is an important consideration when evaluating the clinical end points of hypertension trials.

SYMPLICITY HTN-3 TRIAL: WHAT DID WE LEARN?

As controlling blood pressure is paramount in reducing cardiovascular complications, it is only natural to look for innovative strategies to supplement the medical treatments of hypertension.

The multicenter SYMPLICITY HTN-3 trial¹ was undertaken to establish the efficacy of renal-artery denervation using radiofrequency energy delivered by a catheter-based system (Symplicity RDN, Medtronic, Dublin, Ireland). This randomized, sham-controlled, blinded study did not show a benefit from this procedure with respect to either of its efficacy end points—at 6 months, a reduction in office systolic blood pressure of at least 5 mm Hg more than with medical therapy alone, or a reduction in mean ambulatory systolic pressure of at least 2 mm Hg more than with medical therapy alone.

Despite the negative results, this medium-size (N = 535) randomized clinical trial still represents the highest-level evidence in the field, and we ought to learn something from it.

Limitations of SYMPLICITY HTN-3

Several factors may have contributed to the negative results of the trial. 

Patient selection. For the most part, patients enrolled in renal denervation trials, including SYMPLICITY HTN-3, were not selected on the basis of heightened sympathetic nervous system activity. Assessment of sympathetic nervous system activity may identify the population most likely to achieve an adequate response.

Of note, the baseline blood pressure readings of patients in this trial were higher in the office than on ambulatory monitoring. Patients with white coat hypertension have increased sympathetic nervous system activity and thus might actually be good candidates for renal denervation therapy.

Adequacy of ablation was not measured. Many argue that an objective measure of the adequacy of the denervation procedure (qualitative or quantitative) should have been implemented and, if it had been, the results might have been different. For example, when ablation is performed in the main renal artery as well as the branches, the efficacy in reducing levels of norepinephrine is improved.¹³

Blood pressure fell in both groups. In SYMPLICITY HTN-3 and many other renal denervation trials, patients were assessed using both office and ambulatory blood pressure measurements. The primary end point was the office blood pressure measurement, with a 5-mm Hg difference in reduction chosen to define the superiority margin. This margin was chosen because even small reductions in blood pressure are known to decrease adverse events caused by hypertension. Notably, blood pressure fell significantly in both the control and intervention groups, with an intergroup difference of 2.39 mm Hg (not statistically significant) in favor of denervation.

Medication questions. The SYMPLICITY HTN-3 patients were supposed to be on stable medical regimens with maximal tolerated doses before the procedure. However, it was difficult to assess patients’ adherence to and tolerance of medical therapies. Many (about 40%) of the patients had their medications changed during the study.¹

Therefore, a critical look at the study enrollment criteria may shed more light on the reasons for the negative findings. Did these patients truly have resistant hypertension? Before they underwent the treatment, was their prestudy pharmacologic regimen adequately intensified?

After the findings of the SYMPLICITY HTN-3 study were released, several other trials—such as the Renal Denervation for Hypertension (DENERHTN)¹⁴ and Prague-15 trials¹⁵—reported conflicting results. Notably, these were not sham-controlled trials.

Newer studies with robust trial designs are ongoing. A quick search of www.clinicaltrials.gov reveals that at least 89 active clinical trials of renal denervation are registered as of the date of this writing. Excluding those with unknown status, there are 63 trials open or ongoing.

Clinical trials are also ongoing to determine the effects of renal denervation in patients with heart failure, atrial fibrillation, sleep apnea, and chronic kidney disease, all of which are known to involve heightened sympathetic nervous system activity.

NOT READY FOR CLINICAL USE

Although nonpharmacologic treatments of hypertension continue to be studied and are supported by an avalanche of trials in animals and small, mostly nonrandomized trials in humans, one should not forget that the SYMPLICITY HTN-3 trial simply did not meet its primary efficacy end points. We need definitive clinical evidence showing that renal denervation reduces either blood pressure or clinical events before it becomes a mainstream therapy in humans.

Additional trials are being conducted that were designed in accordance with the recommendations of the European Clinical Consensus Conference for Renal Denervation¹⁶ in terms of study population, design, and end points. Well-designed studies that conform to those recommendations are critical.

Finally, although our enthusiasm for renal denervation as a treatment of hypertension is tempered, there have been no noteworthy safety concerns related to the procedure, which certainly helps maintain the research momentum in this field.              

When renal sympathetic denervation, an endovascular procedure designed to treat resistant hypertension, failed to meet its efficacy goal in the SYMPLICITY HTN-3 trial,¹ the news was disappointing.

See related article

In this issue of the Cleveland Clinic Journal of Medicine, Shishehbor et al² provide a critical review of the findings of that trial and summarize its intricacies, as well as the results of other important trials of renal denervation therapy for hypertension. To their excellent observations, we would like to add some of our own.

HYPERTENSION: COMMON, OFTEN RESISTANT

The worldwide prevalence of hypertension is increasing. In the year 2000, about 26% of the adult world population had hypertension; by the year 2025, the number is projected to rise to 29%—1.56 billion people.³

Only about 50% of patients with hypertension are treated for it and, of those, about half have it adequately controlled. In one report, about 30% of US patients with hypertension had adequate blood pressure control.⁴

Patients who have uncontrolled hypertension are usually older and more obese, have higher baseline blood pressure and excessive salt intake, and are more likely to have chronic kidney disease, diabetes, obstructive sleep apnea, and aldosterone excess.⁵ Many of these conditions are also associated with increased sympathetic nervous system activity.⁶

Resistance and pseudoresistance

But lack of control of blood pressure is not the same as resistant hypertension. It is important to differentiate resistant hypertension from pseudoresistant hypertension, ie, hypertension that only seems to be resistant.⁷ Resistant hypertension affects 12.8% of all drug-treated hypertensive patients in the United States, according to data from the National Health and Nutrition Examination Survey.⁸

Factors that can cause pseudoresistant hypertension include:

Suboptimal antihypertensive regimens (truly resistant hypertension means blood pressure that remains high despite concurrent treatment with 3 antihypertensive drugs of different classes, 1 of which is a diuretic, in maximal doses)

The white coat effect (higher blood pressure in the office than at home, presumably due to the stress of an office visit)

• Suboptimal blood pressure measurement techniques (eg, use of a cuff that is too small, causing falsely high readings)
• Physician inertia (eg, failure to change a regimen that is not working)
• Lifestyle factors (eg, excessive sodium intake)
• Medications that interfere with blood pressure control (eg, nonsteroidal anti-inflammatory drugs)
• Poor adherence to prescribed medications.

Causes of secondary hypertension such as obstructive sleep apnea, primary aldosteronism, and renal artery stenosis should also be ruled out before concluding that a patient has resistant hypertension.

Hypertension causes a myriad of medical diseases, including accelerated atherosclerosis, myocardial ischemia and infarction, both systolic and diastolic heart failure, rhythm problems (eg, atrial fibrillation), and stroke.

Most patients with resistant hypertension have no identifiable reversible causes of it, exhibit increased sympathetic nervous system activity, and have increased risk of cardiovascular events. The risk can be reduced by treatment.^9,10

Adequate and sustained treatment of hypertension prevents and mitigates its complications. The classic Veterans Administration Cooperative Study in the 1960s demonstrated a 96% reduction in cardiovascular events over 18 months with the use of 3 antihypertensive medications in patients with severe hypertension.¹¹ A reduction of as little as 2 mm Hg in the mean blood pressure has been associated with a 10% reduction in the risk of stroke mortality and a 7% decrease in ischemic heart disease mortality.¹² This is an important consideration when evaluating the clinical end points of hypertension trials.

SYMPLICITY HTN-3 TRIAL: WHAT DID WE LEARN?

As controlling blood pressure is paramount in reducing cardiovascular complications, it is only natural to look for innovative strategies to supplement the medical treatments of hypertension.

The multicenter SYMPLICITY HTN-3 trial¹ was undertaken to establish the efficacy of renal-artery denervation using radiofrequency energy delivered by a catheter-based system (Symplicity RDN, Medtronic, Dublin, Ireland). This randomized, sham-controlled, blinded study did not show a benefit from this procedure with respect to either of its efficacy end points—at 6 months, a reduction in office systolic blood pressure of at least 5 mm Hg more than with medical therapy alone, or a reduction in mean ambulatory systolic pressure of at least 2 mm Hg more than with medical therapy alone.

Despite the negative results, this medium-size (N = 535) randomized clinical trial still represents the highest-level evidence in the field, and we ought to learn something from it.

Limitations of SYMPLICITY HTN-3

Several factors may have contributed to the negative results of the trial. 

Patient selection. For the most part, patients enrolled in renal denervation trials, including SYMPLICITY HTN-3, were not selected on the basis of heightened sympathetic nervous system activity. Assessment of sympathetic nervous system activity may identify the population most likely to achieve an adequate response.

Of note, the baseline blood pressure readings of patients in this trial were higher in the office than on ambulatory monitoring. Patients with white coat hypertension have increased sympathetic nervous system activity and thus might actually be good candidates for renal denervation therapy.

Adequacy of ablation was not measured. Many argue that an objective measure of the adequacy of the denervation procedure (qualitative or quantitative) should have been implemented and, if it had been, the results might have been different. For example, when ablation is performed in the main renal artery as well as the branches, the efficacy in reducing levels of norepinephrine is improved.¹³

Blood pressure fell in both groups. In SYMPLICITY HTN-3 and many other renal denervation trials, patients were assessed using both office and ambulatory blood pressure measurements. The primary end point was the office blood pressure measurement, with a 5-mm Hg difference in reduction chosen to define the superiority margin. This margin was chosen because even small reductions in blood pressure are known to decrease adverse events caused by hypertension. Notably, blood pressure fell significantly in both the control and intervention groups, with an intergroup difference of 2.39 mm Hg (not statistically significant) in favor of denervation.

Medication questions. The SYMPLICITY HTN-3 patients were supposed to be on stable medical regimens with maximal tolerated doses before the procedure. However, it was difficult to assess patients’ adherence to and tolerance of medical therapies. Many (about 40%) of the patients had their medications changed during the study.¹

Therefore, a critical look at the study enrollment criteria may shed more light on the reasons for the negative findings. Did these patients truly have resistant hypertension? Before they underwent the treatment, was their prestudy pharmacologic regimen adequately intensified?

After the findings of the SYMPLICITY HTN-3 study were released, several other trials—such as the Renal Denervation for Hypertension (DENERHTN)¹⁴ and Prague-15 trials¹⁵—reported conflicting results. Notably, these were not sham-controlled trials.

Newer studies with robust trial designs are ongoing. A quick search of www.clinicaltrials.gov reveals that at least 89 active clinical trials of renal denervation are registered as of the date of this writing. Excluding those with unknown status, there are 63 trials open or ongoing.

Clinical trials are also ongoing to determine the effects of renal denervation in patients with heart failure, atrial fibrillation, sleep apnea, and chronic kidney disease, all of which are known to involve heightened sympathetic nervous system activity.

NOT READY FOR CLINICAL USE

Although nonpharmacologic treatments of hypertension continue to be studied and are supported by an avalanche of trials in animals and small, mostly nonrandomized trials in humans, one should not forget that the SYMPLICITY HTN-3 trial simply did not meet its primary efficacy end points. We need definitive clinical evidence showing that renal denervation reduces either blood pressure or clinical events before it becomes a mainstream therapy in humans.

Additional trials are being conducted that were designed in accordance with the recommendations of the European Clinical Consensus Conference for Renal Denervation¹⁶ in terms of study population, design, and end points. Well-designed studies that conform to those recommendations are critical.

Finally, although our enthusiasm for renal denervation as a treatment of hypertension is tempered, there have been no noteworthy safety concerns related to the procedure, which certainly helps maintain the research momentum in this field.