Mehdi H. Shishehbor, DO, MPH, PhD

Many patients, clinicians, and researchers had hoped that renal denervation would help control resistant hypertension. However, in the SYMPLICITY HTN-3 trial,¹ named for the catheter-based system used in the study (Symplicity RDN, Medtronic, Dublin, Ireland), this endovascular procedure failed to meet its primary and secondary efficacy end points, although it was found to be safe. These results were surprising, especially given the results of an earlier randomized trial (SYMPLICITY HTN-2),² which showed larger reductions in blood pressures 6 months after denervation than in the current trial.

See related editorial

Here, we discuss the results of the SYMPLICITY HTN-3 trial and offer possible explanations for its negative outcomes.

LEAD-UP TO SYMPLICITY HTN-3

Renal denervation consists of passing a catheter through the femoral artery into the renal arteries and ablating their sympathetic nerves using radiofrequency energy. In theory, this should interrupt efferent sympathetic communication between the brain and renal arteries, reducing muscular contraction of these arteries, increasing renal blood flow, reducing activation of the renin-angiotensin-adosterone system, thus reducing sodium retention, reducing afferent sympathetic communication between the kidneys and brain, and in turn reducing further sympathetic activity elsewhere in the body, such as in the heart. Blood pressure should fall.³

The results of the SYMPLICITY HTN-1 and 2 trials were discussed in an earlier article in this Journal,³ and the Medtronic-Ardian renal denervation system has been available in Europe and Australia for clinical use for over 2 years.⁴ Indeed, after the SYMPLICITY HTN-2 results were published in 2010, Boston Scientific’s Vessix, St. Jude Medical’s EnligHTN, and Covidien’s OneShot radiofrequency renal denervation devices—albeit each with some modifications—received a Conformité Européene (CE) mark and became available in Europe and Australia for clinical use. These devices are not available for clinical use or research in the United States.^3,5

Therefore, SYMPLICITY HTN-3, sponsored by Medtronic, was designed to obtain US Food and Drug Administration approval in the United States.⁶

SYMPLICITY HTN-3 DESIGN

Inclusion criteria were similar to those in the earlier SYMPLICITY trials. Patients had to have resistant hypertension, defined as a systolic blood pressure ≥ 160 mm Hg despite taking at least 3 blood pressure medications at maximum tolerated doses. Patients were excluded if they had a glomerular filtration rate of less than 45 mL/min/1.73 m², renal artery stenosis, or known secondary hypertension.

A total of 1,441 patients were enrolled, of whom 364 were eventually randomized to undergo renal denervation, and 171 were randomized to undergo a sham procedure. The mean systolic blood pressure at baseline was 188 mm Hg in each group. Most patients were taking maximum doses of blood pressure medications, and almost one-fourth were taking an aldosterone antagonist. Patients in both groups were taking an average of 5 medications.

The 2 groups were well matched for important covariates, including obstructive sleep apnea, diabetes mellitus, and renal insufficiency. Most of the patients were white; 25% of the renal denervation group and 29% of the sham procedure group were black.

The physicians conducting the follow-up appointments did not know which procedure the patients underwent, and neither did the patients. Medications were closely monitored, and patients had close follow-up. The catheter (Symplicity RDS, Medtronic) was of the same design that was used in the earlier SYMPLICITY trials and in clinical practice in countries where renal denervation was available.

Researchers expected that the systolic blood pressure, as measured in the office, would fall in both groups, but they hoped it would fall farther in the denervation group—at least 5 mm Hg farther, the primary end point of the trial. The secondary effectiveness end point was a 2-mm Hg greater reduction in 24-hour ambulatory systolic blood pressure.

No statistically significant difference in safety was observed between the denervation and control groups. However, the procedure was associated with 1 embolic event and 1 case of renal artery stenosis.

Blood pressure fell in both groups. However, at 6 months, office systolic pressure had fallen by a mean of 14.13 mm Hg in the denervation group and 11.74 mm Hg in the sham procedure group, a difference of only 2.39 mm Hg. The mean ambulatory systolic blood pressure had fallen by 6.75 vs 4.79 mm Hg, a difference of only 1.96 mm Hg. Neither difference was statistically significant.

A number of prespecified subgroup analyses were conducted, but the benefit of the procedure was statistically significant in only 3 subgroups: patients who were not black (P = .01), patients who were less than 65 years old (P = .04), and patients who had an estimated glomerular filtration rate of 60 mL/min/1.73 m² or higher (P = .05).

WHAT WENT WRONG?

The results of SYMPLICITY HTN-3 were disappointing and led companies that were developing renal denervation devices to discontinue or reevaluate their programs.

Although the results were surprising, many observers (including our group) raised concerns about the initial enthusiasm surrounding renal denervation.^3–7 Indeed, in 2010, we had concerns about the discrepancy between office-based blood pressure measurements (the primary end point of all renal denervation trials) and ambulatory blood pressure measurements in SYMPLICITY HTN-2.⁷

The enthusiasm surrounding this procedure led to the publication of 2 consensus documents on this novel therapy based on only 1 small randomized controlled study (SYMPLICITY HTN-2).^8,9 Renal denervation was even reported to be useful in other conditions involving the sympathorenal axis, including diabetes mellitus, metabolic syndrome, and obstructive sleep apnea, and also as a potential treatment adjunct in atrial fibrillation and other arrhythmias.⁵

What went wrong?

Shortcomings in trial design?

The trial was well designed. Both patients and operators were blinded to the procedure, and 24-hour ambulatory blood pressure monitoring was used. We presume that appropriate patients with resistant hypertension were enrolled—the mean baseline systolic blood pressure was 188 mm Hg, and patients in each group were taking an average of 5 medications.

On the other hand, true medication adherence is difficult to ascertain. Further, the term maximal “tolerated” doses of medications is vague, and we cannot rule out the possibility that some patients were enrolled who did not truly have resistant hypertension—they simply did not want to take medications.

Patients were required to be on a stable medication regimen before enrollment and, ideally, to not have any medication changes during the course of the study, but at least 40% of patients did require medication changes during the study. Additionally, it is unclear whether all patients underwent specific testing to rule out secondary hypertension, as this was done at the discretion of the treating physician.

First-generation catheters?

The same type of catheter was used as in the earlier SYMPLICITY trials, and it had been used in many patients in clinical practice in countries where the catheter is routinely available. It is unknown, however, whether newer multisite denervation devices would yield better results than the first-generation devices used in SYMPLICITY HTN-3. But even this would not explain the discrepancies in data between earlier trials and this trial.

Operator inexperience?

It has been suggested that operator inexperience may have played a role, but an analysis of operator volume did not find any association between this variable and the outcomes. Each procedure was supervised by at least 1 and in most cases 2 certified Medtronic representatives, who made certain that meticulous attention was paid to procedure details and that no shortcuts were taken during the procedure.

Inadequate ablation?

While we can assume that the correct technique was followed in most cases, renal denervation is still a “blind” procedure, and there is no nerve mapping to ascertain the degree of ablation achieved. Notably, patients who had the most ablations reportedly had a greater average drop in systolic ambulatory blood pressure than those who received fewer ablations. Sympathetic nervous system activity is a potential marker of adequacy of ablation, but it was not routinely assessed in the SYMPLICITY HTN-3 trial. Techniques to assess sympathetic nerve activity such as norepinephrine spillover and muscle sympathetic nerve activity are highly specialized and available only at a few research centers, and are not available for routine clinical use.

While these points may explain the negative findings of this trial, they fail to account for the discrepant results between this study and previous trials that used exactly the same definitions and techniques.

Is it possible that renal denervation has a differential effect according to race? All previous renal denervation studies were conducted in Europe or Australia; therefore, few data are available on the efficacy of the procedure in other racial groups, such as black Americans. Most of the patients in this trial were white, but approximately 25% were black—a good representation. There was a statistically significant benefit favoring renal denervation in nonblack (mostly white) patients, but not in black patients. This may be related to racial differences in the pathophysiology of hypertension or possibly due to chance alone.

A Hawthorne effect?

A Hawthorne effect (patients being more compliant because physicians are paying more attention to them) is unlikely, since the renal denervation arm did not have any reduction in blood pressure medications. At 6 months, both the sham group and the procedure group were still on an average of 5 medications.

Additionally, while the blood pressure reduction in both treatment groups was significant, the systolic blood pressure at 6 months was still 166 mm Hg in the denervation group and 168 mm Hg in the sham group. If denervation was effective, one would have expected a greater reduction in blood pressure or at least a decrease in the number of medications needed, eg, 1 to 2 fewer medications in the denervation group compared with the sham procedure group.

Regression to the mean?

It is unknown whether the results represent a statistical error such as regression to the mean. But given the run-in period and the confirmatory data from 24-hour ambulatory blood pressure, this would be unlikely.

WHAT NOW?

Is renal denervation dead? SYMPLICITY HTN-3 is only a single trial with multiple shortcomings and lessons to learn from. Since its publication, there have been updates from 2 prospective, randomized, open-label trials concerning the efficacy of catheter-based renal denervation in lowering blood pressure.^10,11

DENERHTN (Renal Denervation for Hypertension)¹⁰ studied patients with ambulatory systolic blood pressure higher than 135 mm Hg, diastolic blood pressure higher than 80 mm Hg, or both (after excluding secondary etiologies), despite 4 weeks of standardized triple-drug treatment including a diuretic. Patients were randomized to standardized stepped-care antihypertensive treatment alone (control group) or standard care plus renal denervation. The latter resulted in a significant further reduction in ambulatory blood pressure at 6 months.

The Prague-15 trial¹¹ studied patients with resistant hypertension. Secondary etiologies were excluded and adherence to therapy was confirmed by measuring plasma medication levels. It showed that renal denervation along with optimal antihypertensive medical therapy (unchanged after randomization) resulted in a significant reduction in ambulatory blood pressure that was comparable to the effect of intensified antihypertensive medical therapy including spironolactone. (Studies have shown that spironolactone is effective when added on as a fourth-line medication in resistant hypertension.¹²) At 6 months, patients in the intensive medical therapy group were using an average of 0.3 more antihypertensive medications than those in the procedure group.

These two trials addressed some of the drawbacks of the SYMPLICITY HTN-3 trial. However, both have many limitations including and not limited to being open-label and nonblinded, lacking a sham procedure, using a lower blood pressure threshold than SYMPLICITY HTN-3 did to define resistant hypertension, and using the same catheter as in the SYMPLICITY trials.

Advanced renal denervation catheters are needed that are multielectrode, smaller, easier to manipulate, and capable of providing simultaneous, circumferential, more-intense, and deeper ablations. The ongoing Investigator-Steered Project on Intravascular Renal Denervation for Management of Drug-Resistant Hypertension (INSPIRED)¹⁶ and Renal Denervation Using the Vessix Renal Denervation System for the Treatment of Hypertension (REDUCE-HTN: REINFORCE)¹⁷ trials are using contemporary innovative ablation catheters to address the limitations of the first-generation Symplicity catheter.

Further, Fischell et al¹⁸ reported encouraging results of renal denervation performed by injecting ethanol into the adventitial space of the renal arteries. This is still an invasive procedure; however, ethanol can spread out in all directions and reach all targeted nerves, potentially resulting in a more complete renal artery sympathetic ablation.

As technology advances, the WAVE IV trial¹⁹ is examining renal denervation performed from the outside through the skin using high-intensity focused ultrasound, which eliminates the need for femoral arterial catheterization, a promising noninvasive approach.

Proposals for future trials

The European Clinical Consensus Conference for Renal Denervation²⁰ proposed that future trials of renal denervation include patients with moderate rather than resistant hypertension, reflecting the pathogenic importance of sympathetic activity in earlier stages of hypertension. The conference also proposed excluding patients with stiff large arteries, a cause of isolated systolic hypertension. Other proposals included standardizing concomitant antihypertensive therapy, preferably treating all patients with the combination of a renin-angiotensin system blocker, calcium channel blocker, and diuretic in the run-in period; monitoring drug adherence through the use of pill counts, electronic pill dispensers, and drug blood tests; and using change in ambulatory blood pressure as the primary efficacy end point and change in office blood pressure as a secondary end point.

Trials ongoing

To possibly address the limitations posed by the SYMPLICITY HTN-3 trial and to answer other important questions, several sham-controlled clinical trials of renal denervation are currently being conducted:

• INSPiRED¹⁶
• REDUCE-HTN: REINFORCE¹⁷
• Spyral HTN-Off Med²¹
• Spyral HTN-On Med²¹
• Study of the ReCor Medical Paradise System in Clinical Hypertension (RADIANCE-HTN).²²

We hope these new studies can more clearly identify subsets of patients who would benefit from this technology, determine predictors of blood pressure reduction in such patients, and lead to newer devices that may provide more complete ablation.

Obviously, we also need better ways to identify the exact location of these sympathetic nerves within the renal artery and have a clearer sense of procedural success.

Until then, our colleagues in Europe and Australia continue to treat patients with this technology as we appropriately and patiently wait for level 1 clinical evidence of its efficacy.

Acknowledgments: We thank Kathryn Brock, BA, Editorial Services Manager, Heart and Vascular Institute, Cleveland Clinic, for her assistance in the preparation of this paper.

Many patients, clinicians, and researchers had hoped that renal denervation would help control resistant hypertension. However, in the SYMPLICITY HTN-3 trial,¹ named for the catheter-based system used in the study (Symplicity RDN, Medtronic, Dublin, Ireland), this endovascular procedure failed to meet its primary and secondary efficacy end points, although it was found to be safe. These results were surprising, especially given the results of an earlier randomized trial (SYMPLICITY HTN-2),² which showed larger reductions in blood pressures 6 months after denervation than in the current trial.

See related editorial

Here, we discuss the results of the SYMPLICITY HTN-3 trial and offer possible explanations for its negative outcomes.

LEAD-UP TO SYMPLICITY HTN-3

Renal denervation consists of passing a catheter through the femoral artery into the renal arteries and ablating their sympathetic nerves using radiofrequency energy. In theory, this should interrupt efferent sympathetic communication between the brain and renal arteries, reducing muscular contraction of these arteries, increasing renal blood flow, reducing activation of the renin-angiotensin-adosterone system, thus reducing sodium retention, reducing afferent sympathetic communication between the kidneys and brain, and in turn reducing further sympathetic activity elsewhere in the body, such as in the heart. Blood pressure should fall.³

The results of the SYMPLICITY HTN-1 and 2 trials were discussed in an earlier article in this Journal,³ and the Medtronic-Ardian renal denervation system has been available in Europe and Australia for clinical use for over 2 years.⁴ Indeed, after the SYMPLICITY HTN-2 results were published in 2010, Boston Scientific’s Vessix, St. Jude Medical’s EnligHTN, and Covidien’s OneShot radiofrequency renal denervation devices—albeit each with some modifications—received a Conformité Européene (CE) mark and became available in Europe and Australia for clinical use. These devices are not available for clinical use or research in the United States.^3,5

Therefore, SYMPLICITY HTN-3, sponsored by Medtronic, was designed to obtain US Food and Drug Administration approval in the United States.⁶

SYMPLICITY HTN-3 DESIGN

Inclusion criteria were similar to those in the earlier SYMPLICITY trials. Patients had to have resistant hypertension, defined as a systolic blood pressure ≥ 160 mm Hg despite taking at least 3 blood pressure medications at maximum tolerated doses. Patients were excluded if they had a glomerular filtration rate of less than 45 mL/min/1.73 m², renal artery stenosis, or known secondary hypertension.

A total of 1,441 patients were enrolled, of whom 364 were eventually randomized to undergo renal denervation, and 171 were randomized to undergo a sham procedure. The mean systolic blood pressure at baseline was 188 mm Hg in each group. Most patients were taking maximum doses of blood pressure medications, and almost one-fourth were taking an aldosterone antagonist. Patients in both groups were taking an average of 5 medications.

The 2 groups were well matched for important covariates, including obstructive sleep apnea, diabetes mellitus, and renal insufficiency. Most of the patients were white; 25% of the renal denervation group and 29% of the sham procedure group were black.

The physicians conducting the follow-up appointments did not know which procedure the patients underwent, and neither did the patients. Medications were closely monitored, and patients had close follow-up. The catheter (Symplicity RDS, Medtronic) was of the same design that was used in the earlier SYMPLICITY trials and in clinical practice in countries where renal denervation was available.

Researchers expected that the systolic blood pressure, as measured in the office, would fall in both groups, but they hoped it would fall farther in the denervation group—at least 5 mm Hg farther, the primary end point of the trial. The secondary effectiveness end point was a 2-mm Hg greater reduction in 24-hour ambulatory systolic blood pressure.

No statistically significant difference in safety was observed between the denervation and control groups. However, the procedure was associated with 1 embolic event and 1 case of renal artery stenosis.

Blood pressure fell in both groups. However, at 6 months, office systolic pressure had fallen by a mean of 14.13 mm Hg in the denervation group and 11.74 mm Hg in the sham procedure group, a difference of only 2.39 mm Hg. The mean ambulatory systolic blood pressure had fallen by 6.75 vs 4.79 mm Hg, a difference of only 1.96 mm Hg. Neither difference was statistically significant.

A number of prespecified subgroup analyses were conducted, but the benefit of the procedure was statistically significant in only 3 subgroups: patients who were not black (P = .01), patients who were less than 65 years old (P = .04), and patients who had an estimated glomerular filtration rate of 60 mL/min/1.73 m² or higher (P = .05).

WHAT WENT WRONG?

The results of SYMPLICITY HTN-3 were disappointing and led companies that were developing renal denervation devices to discontinue or reevaluate their programs.

Although the results were surprising, many observers (including our group) raised concerns about the initial enthusiasm surrounding renal denervation.^3–7 Indeed, in 2010, we had concerns about the discrepancy between office-based blood pressure measurements (the primary end point of all renal denervation trials) and ambulatory blood pressure measurements in SYMPLICITY HTN-2.⁷

The enthusiasm surrounding this procedure led to the publication of 2 consensus documents on this novel therapy based on only 1 small randomized controlled study (SYMPLICITY HTN-2).^8,9 Renal denervation was even reported to be useful in other conditions involving the sympathorenal axis, including diabetes mellitus, metabolic syndrome, and obstructive sleep apnea, and also as a potential treatment adjunct in atrial fibrillation and other arrhythmias.⁵

What went wrong?

Shortcomings in trial design?

The trial was well designed. Both patients and operators were blinded to the procedure, and 24-hour ambulatory blood pressure monitoring was used. We presume that appropriate patients with resistant hypertension were enrolled—the mean baseline systolic blood pressure was 188 mm Hg, and patients in each group were taking an average of 5 medications.

On the other hand, true medication adherence is difficult to ascertain. Further, the term maximal “tolerated” doses of medications is vague, and we cannot rule out the possibility that some patients were enrolled who did not truly have resistant hypertension—they simply did not want to take medications.

Patients were required to be on a stable medication regimen before enrollment and, ideally, to not have any medication changes during the course of the study, but at least 40% of patients did require medication changes during the study. Additionally, it is unclear whether all patients underwent specific testing to rule out secondary hypertension, as this was done at the discretion of the treating physician.

First-generation catheters?

The same type of catheter was used as in the earlier SYMPLICITY trials, and it had been used in many patients in clinical practice in countries where the catheter is routinely available. It is unknown, however, whether newer multisite denervation devices would yield better results than the first-generation devices used in SYMPLICITY HTN-3. But even this would not explain the discrepancies in data between earlier trials and this trial.

Operator inexperience?

It has been suggested that operator inexperience may have played a role, but an analysis of operator volume did not find any association between this variable and the outcomes. Each procedure was supervised by at least 1 and in most cases 2 certified Medtronic representatives, who made certain that meticulous attention was paid to procedure details and that no shortcuts were taken during the procedure.

Inadequate ablation?

While we can assume that the correct technique was followed in most cases, renal denervation is still a “blind” procedure, and there is no nerve mapping to ascertain the degree of ablation achieved. Notably, patients who had the most ablations reportedly had a greater average drop in systolic ambulatory blood pressure than those who received fewer ablations. Sympathetic nervous system activity is a potential marker of adequacy of ablation, but it was not routinely assessed in the SYMPLICITY HTN-3 trial. Techniques to assess sympathetic nerve activity such as norepinephrine spillover and muscle sympathetic nerve activity are highly specialized and available only at a few research centers, and are not available for routine clinical use.

While these points may explain the negative findings of this trial, they fail to account for the discrepant results between this study and previous trials that used exactly the same definitions and techniques.

Is it possible that renal denervation has a differential effect according to race? All previous renal denervation studies were conducted in Europe or Australia; therefore, few data are available on the efficacy of the procedure in other racial groups, such as black Americans. Most of the patients in this trial were white, but approximately 25% were black—a good representation. There was a statistically significant benefit favoring renal denervation in nonblack (mostly white) patients, but not in black patients. This may be related to racial differences in the pathophysiology of hypertension or possibly due to chance alone.

A Hawthorne effect?

A Hawthorne effect (patients being more compliant because physicians are paying more attention to them) is unlikely, since the renal denervation arm did not have any reduction in blood pressure medications. At 6 months, both the sham group and the procedure group were still on an average of 5 medications.

Additionally, while the blood pressure reduction in both treatment groups was significant, the systolic blood pressure at 6 months was still 166 mm Hg in the denervation group and 168 mm Hg in the sham group. If denervation was effective, one would have expected a greater reduction in blood pressure or at least a decrease in the number of medications needed, eg, 1 to 2 fewer medications in the denervation group compared with the sham procedure group.

Regression to the mean?

It is unknown whether the results represent a statistical error such as regression to the mean. But given the run-in period and the confirmatory data from 24-hour ambulatory blood pressure, this would be unlikely.

WHAT NOW?

Is renal denervation dead? SYMPLICITY HTN-3 is only a single trial with multiple shortcomings and lessons to learn from. Since its publication, there have been updates from 2 prospective, randomized, open-label trials concerning the efficacy of catheter-based renal denervation in lowering blood pressure.^10,11

DENERHTN (Renal Denervation for Hypertension)¹⁰ studied patients with ambulatory systolic blood pressure higher than 135 mm Hg, diastolic blood pressure higher than 80 mm Hg, or both (after excluding secondary etiologies), despite 4 weeks of standardized triple-drug treatment including a diuretic. Patients were randomized to standardized stepped-care antihypertensive treatment alone (control group) or standard care plus renal denervation. The latter resulted in a significant further reduction in ambulatory blood pressure at 6 months.

The Prague-15 trial¹¹ studied patients with resistant hypertension. Secondary etiologies were excluded and adherence to therapy was confirmed by measuring plasma medication levels. It showed that renal denervation along with optimal antihypertensive medical therapy (unchanged after randomization) resulted in a significant reduction in ambulatory blood pressure that was comparable to the effect of intensified antihypertensive medical therapy including spironolactone. (Studies have shown that spironolactone is effective when added on as a fourth-line medication in resistant hypertension.¹²) At 6 months, patients in the intensive medical therapy group were using an average of 0.3 more antihypertensive medications than those in the procedure group.

These two trials addressed some of the drawbacks of the SYMPLICITY HTN-3 trial. However, both have many limitations including and not limited to being open-label and nonblinded, lacking a sham procedure, using a lower blood pressure threshold than SYMPLICITY HTN-3 did to define resistant hypertension, and using the same catheter as in the SYMPLICITY trials.

Advanced renal denervation catheters are needed that are multielectrode, smaller, easier to manipulate, and capable of providing simultaneous, circumferential, more-intense, and deeper ablations. The ongoing Investigator-Steered Project on Intravascular Renal Denervation for Management of Drug-Resistant Hypertension (INSPIRED)¹⁶ and Renal Denervation Using the Vessix Renal Denervation System for the Treatment of Hypertension (REDUCE-HTN: REINFORCE)¹⁷ trials are using contemporary innovative ablation catheters to address the limitations of the first-generation Symplicity catheter.

Further, Fischell et al¹⁸ reported encouraging results of renal denervation performed by injecting ethanol into the adventitial space of the renal arteries. This is still an invasive procedure; however, ethanol can spread out in all directions and reach all targeted nerves, potentially resulting in a more complete renal artery sympathetic ablation.

As technology advances, the WAVE IV trial¹⁹ is examining renal denervation performed from the outside through the skin using high-intensity focused ultrasound, which eliminates the need for femoral arterial catheterization, a promising noninvasive approach.

Proposals for future trials

The European Clinical Consensus Conference for Renal Denervation²⁰ proposed that future trials of renal denervation include patients with moderate rather than resistant hypertension, reflecting the pathogenic importance of sympathetic activity in earlier stages of hypertension. The conference also proposed excluding patients with stiff large arteries, a cause of isolated systolic hypertension. Other proposals included standardizing concomitant antihypertensive therapy, preferably treating all patients with the combination of a renin-angiotensin system blocker, calcium channel blocker, and diuretic in the run-in period; monitoring drug adherence through the use of pill counts, electronic pill dispensers, and drug blood tests; and using change in ambulatory blood pressure as the primary efficacy end point and change in office blood pressure as a secondary end point.

Trials ongoing

To possibly address the limitations posed by the SYMPLICITY HTN-3 trial and to answer other important questions, several sham-controlled clinical trials of renal denervation are currently being conducted:

• INSPiRED¹⁶
• REDUCE-HTN: REINFORCE¹⁷
• Spyral HTN-Off Med²¹
• Spyral HTN-On Med²¹
• Study of the ReCor Medical Paradise System in Clinical Hypertension (RADIANCE-HTN).²²

We hope these new studies can more clearly identify subsets of patients who would benefit from this technology, determine predictors of blood pressure reduction in such patients, and lead to newer devices that may provide more complete ablation.

Obviously, we also need better ways to identify the exact location of these sympathetic nerves within the renal artery and have a clearer sense of procedural success.

Until then, our colleagues in Europe and Australia continue to treat patients with this technology as we appropriately and patiently wait for level 1 clinical evidence of its efficacy.

Acknowledgments: We thank Kathryn Brock, BA, Editorial Services Manager, Heart and Vascular Institute, Cleveland Clinic, for her assistance in the preparation of this paper.

Many patients, clinicians, and researchers had hoped that renal denervation would help control resistant hypertension. However, in the SYMPLICITY HTN-3 trial,¹ named for the catheter-based system used in the study (Symplicity RDN, Medtronic, Dublin, Ireland), this endovascular procedure failed to meet its primary and secondary efficacy end points, although it was found to be safe. These results were surprising, especially given the results of an earlier randomized trial (SYMPLICITY HTN-2),² which showed larger reductions in blood pressures 6 months after denervation than in the current trial.

See related editorial

Here, we discuss the results of the SYMPLICITY HTN-3 trial and offer possible explanations for its negative outcomes.

LEAD-UP TO SYMPLICITY HTN-3

Renal denervation consists of passing a catheter through the femoral artery into the renal arteries and ablating their sympathetic nerves using radiofrequency energy. In theory, this should interrupt efferent sympathetic communication between the brain and renal arteries, reducing muscular contraction of these arteries, increasing renal blood flow, reducing activation of the renin-angiotensin-adosterone system, thus reducing sodium retention, reducing afferent sympathetic communication between the kidneys and brain, and in turn reducing further sympathetic activity elsewhere in the body, such as in the heart. Blood pressure should fall.³

The results of the SYMPLICITY HTN-1 and 2 trials were discussed in an earlier article in this Journal,³ and the Medtronic-Ardian renal denervation system has been available in Europe and Australia for clinical use for over 2 years.⁴ Indeed, after the SYMPLICITY HTN-2 results were published in 2010, Boston Scientific’s Vessix, St. Jude Medical’s EnligHTN, and Covidien’s OneShot radiofrequency renal denervation devices—albeit each with some modifications—received a Conformité Européene (CE) mark and became available in Europe and Australia for clinical use. These devices are not available for clinical use or research in the United States.^3,5

Therefore, SYMPLICITY HTN-3, sponsored by Medtronic, was designed to obtain US Food and Drug Administration approval in the United States.⁶

SYMPLICITY HTN-3 DESIGN

Inclusion criteria were similar to those in the earlier SYMPLICITY trials. Patients had to have resistant hypertension, defined as a systolic blood pressure ≥ 160 mm Hg despite taking at least 3 blood pressure medications at maximum tolerated doses. Patients were excluded if they had a glomerular filtration rate of less than 45 mL/min/1.73 m², renal artery stenosis, or known secondary hypertension.

A total of 1,441 patients were enrolled, of whom 364 were eventually randomized to undergo renal denervation, and 171 were randomized to undergo a sham procedure. The mean systolic blood pressure at baseline was 188 mm Hg in each group. Most patients were taking maximum doses of blood pressure medications, and almost one-fourth were taking an aldosterone antagonist. Patients in both groups were taking an average of 5 medications.

The 2 groups were well matched for important covariates, including obstructive sleep apnea, diabetes mellitus, and renal insufficiency. Most of the patients were white; 25% of the renal denervation group and 29% of the sham procedure group were black.

The physicians conducting the follow-up appointments did not know which procedure the patients underwent, and neither did the patients. Medications were closely monitored, and patients had close follow-up. The catheter (Symplicity RDS, Medtronic) was of the same design that was used in the earlier SYMPLICITY trials and in clinical practice in countries where renal denervation was available.

Researchers expected that the systolic blood pressure, as measured in the office, would fall in both groups, but they hoped it would fall farther in the denervation group—at least 5 mm Hg farther, the primary end point of the trial. The secondary effectiveness end point was a 2-mm Hg greater reduction in 24-hour ambulatory systolic blood pressure.

No statistically significant difference in safety was observed between the denervation and control groups. However, the procedure was associated with 1 embolic event and 1 case of renal artery stenosis.

Blood pressure fell in both groups. However, at 6 months, office systolic pressure had fallen by a mean of 14.13 mm Hg in the denervation group and 11.74 mm Hg in the sham procedure group, a difference of only 2.39 mm Hg. The mean ambulatory systolic blood pressure had fallen by 6.75 vs 4.79 mm Hg, a difference of only 1.96 mm Hg. Neither difference was statistically significant.

A number of prespecified subgroup analyses were conducted, but the benefit of the procedure was statistically significant in only 3 subgroups: patients who were not black (P = .01), patients who were less than 65 years old (P = .04), and patients who had an estimated glomerular filtration rate of 60 mL/min/1.73 m² or higher (P = .05).

WHAT WENT WRONG?

The results of SYMPLICITY HTN-3 were disappointing and led companies that were developing renal denervation devices to discontinue or reevaluate their programs.

Although the results were surprising, many observers (including our group) raised concerns about the initial enthusiasm surrounding renal denervation.^3–7 Indeed, in 2010, we had concerns about the discrepancy between office-based blood pressure measurements (the primary end point of all renal denervation trials) and ambulatory blood pressure measurements in SYMPLICITY HTN-2.⁷

The enthusiasm surrounding this procedure led to the publication of 2 consensus documents on this novel therapy based on only 1 small randomized controlled study (SYMPLICITY HTN-2).^8,9 Renal denervation was even reported to be useful in other conditions involving the sympathorenal axis, including diabetes mellitus, metabolic syndrome, and obstructive sleep apnea, and also as a potential treatment adjunct in atrial fibrillation and other arrhythmias.⁵

What went wrong?

Shortcomings in trial design?

The trial was well designed. Both patients and operators were blinded to the procedure, and 24-hour ambulatory blood pressure monitoring was used. We presume that appropriate patients with resistant hypertension were enrolled—the mean baseline systolic blood pressure was 188 mm Hg, and patients in each group were taking an average of 5 medications.

On the other hand, true medication adherence is difficult to ascertain. Further, the term maximal “tolerated” doses of medications is vague, and we cannot rule out the possibility that some patients were enrolled who did not truly have resistant hypertension—they simply did not want to take medications.

Patients were required to be on a stable medication regimen before enrollment and, ideally, to not have any medication changes during the course of the study, but at least 40% of patients did require medication changes during the study. Additionally, it is unclear whether all patients underwent specific testing to rule out secondary hypertension, as this was done at the discretion of the treating physician.

First-generation catheters?

The same type of catheter was used as in the earlier SYMPLICITY trials, and it had been used in many patients in clinical practice in countries where the catheter is routinely available. It is unknown, however, whether newer multisite denervation devices would yield better results than the first-generation devices used in SYMPLICITY HTN-3. But even this would not explain the discrepancies in data between earlier trials and this trial.

Operator inexperience?

It has been suggested that operator inexperience may have played a role, but an analysis of operator volume did not find any association between this variable and the outcomes. Each procedure was supervised by at least 1 and in most cases 2 certified Medtronic representatives, who made certain that meticulous attention was paid to procedure details and that no shortcuts were taken during the procedure.

Inadequate ablation?

While we can assume that the correct technique was followed in most cases, renal denervation is still a “blind” procedure, and there is no nerve mapping to ascertain the degree of ablation achieved. Notably, patients who had the most ablations reportedly had a greater average drop in systolic ambulatory blood pressure than those who received fewer ablations. Sympathetic nervous system activity is a potential marker of adequacy of ablation, but it was not routinely assessed in the SYMPLICITY HTN-3 trial. Techniques to assess sympathetic nerve activity such as norepinephrine spillover and muscle sympathetic nerve activity are highly specialized and available only at a few research centers, and are not available for routine clinical use.

While these points may explain the negative findings of this trial, they fail to account for the discrepant results between this study and previous trials that used exactly the same definitions and techniques.

Is it possible that renal denervation has a differential effect according to race? All previous renal denervation studies were conducted in Europe or Australia; therefore, few data are available on the efficacy of the procedure in other racial groups, such as black Americans. Most of the patients in this trial were white, but approximately 25% were black—a good representation. There was a statistically significant benefit favoring renal denervation in nonblack (mostly white) patients, but not in black patients. This may be related to racial differences in the pathophysiology of hypertension or possibly due to chance alone.

A Hawthorne effect?

A Hawthorne effect (patients being more compliant because physicians are paying more attention to them) is unlikely, since the renal denervation arm did not have any reduction in blood pressure medications. At 6 months, both the sham group and the procedure group were still on an average of 5 medications.

Additionally, while the blood pressure reduction in both treatment groups was significant, the systolic blood pressure at 6 months was still 166 mm Hg in the denervation group and 168 mm Hg in the sham group. If denervation was effective, one would have expected a greater reduction in blood pressure or at least a decrease in the number of medications needed, eg, 1 to 2 fewer medications in the denervation group compared with the sham procedure group.

Regression to the mean?

It is unknown whether the results represent a statistical error such as regression to the mean. But given the run-in period and the confirmatory data from 24-hour ambulatory blood pressure, this would be unlikely.

WHAT NOW?

Is renal denervation dead? SYMPLICITY HTN-3 is only a single trial with multiple shortcomings and lessons to learn from. Since its publication, there have been updates from 2 prospective, randomized, open-label trials concerning the efficacy of catheter-based renal denervation in lowering blood pressure.^10,11

DENERHTN (Renal Denervation for Hypertension)¹⁰ studied patients with ambulatory systolic blood pressure higher than 135 mm Hg, diastolic blood pressure higher than 80 mm Hg, or both (after excluding secondary etiologies), despite 4 weeks of standardized triple-drug treatment including a diuretic. Patients were randomized to standardized stepped-care antihypertensive treatment alone (control group) or standard care plus renal denervation. The latter resulted in a significant further reduction in ambulatory blood pressure at 6 months.

The Prague-15 trial¹¹ studied patients with resistant hypertension. Secondary etiologies were excluded and adherence to therapy was confirmed by measuring plasma medication levels. It showed that renal denervation along with optimal antihypertensive medical therapy (unchanged after randomization) resulted in a significant reduction in ambulatory blood pressure that was comparable to the effect of intensified antihypertensive medical therapy including spironolactone. (Studies have shown that spironolactone is effective when added on as a fourth-line medication in resistant hypertension.¹²) At 6 months, patients in the intensive medical therapy group were using an average of 0.3 more antihypertensive medications than those in the procedure group.

These two trials addressed some of the drawbacks of the SYMPLICITY HTN-3 trial. However, both have many limitations including and not limited to being open-label and nonblinded, lacking a sham procedure, using a lower blood pressure threshold than SYMPLICITY HTN-3 did to define resistant hypertension, and using the same catheter as in the SYMPLICITY trials.

Advanced renal denervation catheters are needed that are multielectrode, smaller, easier to manipulate, and capable of providing simultaneous, circumferential, more-intense, and deeper ablations. The ongoing Investigator-Steered Project on Intravascular Renal Denervation for Management of Drug-Resistant Hypertension (INSPIRED)¹⁶ and Renal Denervation Using the Vessix Renal Denervation System for the Treatment of Hypertension (REDUCE-HTN: REINFORCE)¹⁷ trials are using contemporary innovative ablation catheters to address the limitations of the first-generation Symplicity catheter.

Further, Fischell et al¹⁸ reported encouraging results of renal denervation performed by injecting ethanol into the adventitial space of the renal arteries. This is still an invasive procedure; however, ethanol can spread out in all directions and reach all targeted nerves, potentially resulting in a more complete renal artery sympathetic ablation.

As technology advances, the WAVE IV trial¹⁹ is examining renal denervation performed from the outside through the skin using high-intensity focused ultrasound, which eliminates the need for femoral arterial catheterization, a promising noninvasive approach.

Proposals for future trials

The European Clinical Consensus Conference for Renal Denervation²⁰ proposed that future trials of renal denervation include patients with moderate rather than resistant hypertension, reflecting the pathogenic importance of sympathetic activity in earlier stages of hypertension. The conference also proposed excluding patients with stiff large arteries, a cause of isolated systolic hypertension. Other proposals included standardizing concomitant antihypertensive therapy, preferably treating all patients with the combination of a renin-angiotensin system blocker, calcium channel blocker, and diuretic in the run-in period; monitoring drug adherence through the use of pill counts, electronic pill dispensers, and drug blood tests; and using change in ambulatory blood pressure as the primary efficacy end point and change in office blood pressure as a secondary end point.

Trials ongoing

To possibly address the limitations posed by the SYMPLICITY HTN-3 trial and to answer other important questions, several sham-controlled clinical trials of renal denervation are currently being conducted:

• INSPiRED¹⁶
• REDUCE-HTN: REINFORCE¹⁷
• Spyral HTN-Off Med²¹
• Spyral HTN-On Med²¹
• Study of the ReCor Medical Paradise System in Clinical Hypertension (RADIANCE-HTN).²²

We hope these new studies can more clearly identify subsets of patients who would benefit from this technology, determine predictors of blood pressure reduction in such patients, and lead to newer devices that may provide more complete ablation.

Obviously, we also need better ways to identify the exact location of these sympathetic nerves within the renal artery and have a clearer sense of procedural success.

Until then, our colleagues in Europe and Australia continue to treat patients with this technology as we appropriately and patiently wait for level 1 clinical evidence of its efficacy.

Acknowledgments: We thank Kathryn Brock, BA, Editorial Services Manager, Heart and Vascular Institute, Cleveland Clinic, for her assistance in the preparation of this paper.

A 43-year-old man presented to a community hospital with acute chest pain and shortness of breath and was diagnosed with anterior ST-elevation myocardial infarction. He was a smoker with a history of alcohol abuse, hypertension, and hyperlipidemia, and in the past he had undergone percutaneous coronary interventions to the right coronary artery and the first obtuse marginal artery.

Angiography showed total occlusion in the left anterior descending artery, 90% stenosis in the right coronary artery, and mild disease in the left circumflex artery. A drug-eluting stent was placed in the left anterior descending artery, resulting in good blood flow. 

However, his left ventricle continued to have severe dysfunction. An intra-aortic balloon pump was inserted. Afterward, computed tomography showed subsegmental pulmonary embolism with congestion. His mean arterial pressure was 60 mm Hg (normal 70–110), central venous pressure 12 mm Hg (3–8), pulmonary artery pressure 38/26 mm Hg (15–30/4–12), pulmonary capillary wedge pressure 24 mm Hg (2–15), and cardiac index 1.4 L/min (2.5–4).

The patient was started on dobutamine and norepinephrine and transferred to Cleveland Clinic on day 2. Over the next day, he had runs of ventricular tachycardia, for which he was given amiodarone and lidocaine. His urine output was low, and his serum creatinine was elevated at 1.65 mg/dL (baseline 1.2, normal 0.5–1.5). Liver function tests were also elevated, with aspartate aminotransferase at 115 U/L(14–40) and alanine aminotransferase at 187 U/L (10–54).

Poor oxygenation was evident: his arterial partial pressure of oxygen was 64 mm Hg (normal 75–100). He was intubated and given 100% oxygen with positive end-expiratory pressure of 12 cm H₂O.

Echocardiography showed a left ventricular ejection fraction of 15% (normal 55%–70%) and mild right ventricular dysfunction.

ECMO and then Impella placement

On his third hospital day, a venoarterial extracorporeal membrane oxygenation (ECMO) device was placed peripherally (Figure 1).

His hemodynamic variables stabilized, and he was weaned off dobutamine and norepinephrine. Results of liver function tests normalized, his urinary output increased, and his serum creatinine dropped to a normal 1.0 mg/dL. However, a chest radiograph showed pulmonary congestion, and echocardiography now showed severe left ventricular dysfunction.

On hospital day 5, the patient underwent surgical placement of an Impella 5.0 device (Abiomed, Danvers, MA) through the right axillary artery in an effort to improve his pulmonary edema. The ECMO device was removed. Placement of a venovenous ECMO device was deemed unnecessary when oxygenation improved with the Impella.

Three days after Impella placement, radiography showed improved edema with some remaining pleural effusion.

ACUTE CARDIOGENIC SHOCK

Cardiogenic shock remains a challenging clinical problem: patients with it are among the sickest in the hospital, and many of them die. ECMO was once the only therapy available and is still widely used. However, it is a 2-edged sword; complications such as bleeding, infection, and thrombosis are almost inevitable if it is used for long. Importantly, patients are usually kept intubated and bedridden.

In recent years, new devices have become available that are easier to place (some in the catheterization laboratory or even at the bedside) and allow safer bridging to recovery, transplant, or other therapies.

This case illustrates the natural history of cardiogenic shock and the preferred clinical approach: ie, ongoing evaluation that permits rapid response to evolving challenges.

In general, acute cardiogenic shock occurs within 24 to 48 hours after the initial insult, so even if a procedure succeeds, the patient may develop progressive hypotension and organ dysfunction. Reduced cardiac output causes a downward spiral with multiple systemic and inflammatory processes as well as increased nitric oxide synthesis, leading to progressive decline and eventual end-organ dysfunction.

Continuously evaluate

The cardiac team should continuously assess the acuity and severity of a patient’s condition, with the goals of maintaining end-organ perfusion and identifying the source of problems. Refractory cardiogenic shock, with tissue hypoperfusion despite vasoactive medications and treatment of the underlying cause, is associated with in-hospital mortality rates ranging from 30% to 50%.^1,2 The rates have actually increased over the past decade, as sicker patients are being treated.

When a patient presents with cardiogenic shock, we first try a series of vasoactive drugs and usually an intra-aortic balloon pump (Figure 2). We then tailor treatment depending on etiology. For example, a patient may have viral myocarditis and may even require a biopsy.

If cardiogenic shock is refractory, mechanical circulatory support devices can be a short-term bridge to either recovery or a new decision. A multidisciplinary team should be consulted to consider transplant, a long-term device, or palliative care. Sometimes a case requires “bridging to a bridge,” with several devices used short-term in turn.

Prognostic factors in cardiogenic shock

Several tools help predict outcome in a severely ill patient. End-organ function, indicated by blood lactate levels and estimated glomerular filtration rate, is perhaps the most informative and should be monitored serially.

CardShock³ is a simple scoring system based on age, mental status at presentation, laboratory values, and medical history. Patients receive 1 point for each of the following factors:

• Age > 75
• Confusion at presentation
• Previous myocardial infarction or coronary artery bypass grafting
• Acute coronary syndrome etiology
• Left ventricular ejection fraction < 40%
• Blood lactate level between 2 and 4 mmol/L, inclusively (2 points for lactate levels > 4 mmol/L)
• Estimated glomerular filtration rate between 30 and 60 mL/min/1.73 m², inclusively (2 points if < 30 mL/min/1.73 m²). 

Thus, scores range from 0 (best) to 9 (worst). A score of 0 to 3 points was associated with a 9% risk of death in the hospital, a score of 4 or 5 with a risk of 36%, and a score of 6 through 9 with a risk of 77%.³

The Survival After Veno-arterial ECMO (SAVE) score (www.save-score.com) is a prediction tool derived from a large international ECMO registry.⁴ It is based on patient age, diagnosis, and indicators of end-organ dysfunction. Scores range from –35 (worst) to +7 (best).

The mortality rate associated with postcardiotomy cardiogenic shock increases with the amount of inotropic support provided. In a 1996–1999 case series of patients who underwent open-heart surgery,⁵ the hospital mortality rate was 40% in those who received 2 inotropes in high doses and 80% in those who received 3. A strategy of early implementation of mechanical support is critical.

Selection criteria for destination therapy

Deciding whether a patient should receive a long-term device is frequently a challenge. The decision often must be based on limited information about not only the medical indications but also psychosocial factors that influence long-term success.

The Centers for Medicare and Medicaid Services have established criteria for candidates for left ventricular assist devices (LVADs) as destination therapy.⁶ Contraindications established for heart transplant should also be considered (Table 1).

CASE REVISITED

Several factors argued against LVAD placement in our patient. He had no health insurance and had been off medications. He smoked and said he consumed 3 hard liquor drinks per week. His Stanford Integrated Psychosocial Assessment for Transplantation score was 30 (minimally acceptable). He had hypoxia with subsegmental pulmonary edema, a strong contraindication to immediate transplant.

On the other hand, he had only mild right ventricular dysfunction. His CardShock score was 4 (intermediate risk, based on lactate 1.5 mmol/L and estimated glomerular filtration rate 52 mL/min/1.73 m²). His SAVE score was –9 (class IV), which overall is associated with a 30% risk of death (low enough to consider treatment).

During the patient’s time on temporary support, the team had the opportunity to better understand him and assess his family support and his ability to handle a permanent device. His surviving the acute course bolstered the team’s confidence that he could enjoy long-term survival with destination therapy.

CATHETERIZATION LABORATORY DEVICE CAPABILITIES

Although most implantation procedures are done in the operating room, they are often done in the catheterization laboratory because patients undergoing catheterization may not be stable enough for transfer, or an emergency intervention may be required during the night. Catheterization interventionists are also an important part of the team to help determine the best approach for long-term therapy.

The catheterization laboratory has multiple acute intervention options. Usually, decisions must be made quickly. In general, patients needing mechanical support are managed as follows:

• Those who need circulation support and oxygenation receive ECMO
• Those who need circulation support alone because of mechanical issues (eg, myocardial infarction) are considered for an intra-aortic balloon pump, Impella, or TandemHeart pump (Cardiac Assist, Pittsburgh, PA).

Factors that guide the selection of a temporary pump include:

• Left ventricular function
• Right ventricular function
• Aortic valve stenosis (some devices cannot be inserted through critical aortic stenosis)
• Aortic regurgitation (can affect some devices)
• Peripheral artery disease (some devices are large and must be placed percutaneously).

CHOOSING AMONG PERCUTANEOUS DEVICES

Circulatory support in cardiogenic shock improves outcomes, and devices play an important role in supporting high-risk procedures. The goal is not necessarily to use the device throughout the hospital stay. Acute stabilization is most important initially; a more considered decision about long-term therapy can be made when more is known about the patient.

Patient selection is the most important component of success. However, randomized data to support outcomes with the various devices are sparse and complicated by the critically ill state of the patient population.

SHORT-TERM CIRCULATORY SUPPORT: ECMO, IMPELLA, TANDEMHEART

A menu of options is available for temporary mechanical support. Options differ by their degree of circulatory support and ease of insertion (Table 2).

ECMO: A fast option with many advantages

ECMO has evolved and now can be placed quickly. A remote diagnostic platform such as CardioHub permits management at the bedside, in the medical unit, or in the cardiac intensive care unit.⁷

ECMO has several advantages. It can be used during cardiopulmonary bypass, it provides oxygenation, it is the only option in the setting of lung injury, it can be placed peripherally (without thoracotomy), and it is the only percutaneous option for biventricular support.

ECMO also has significant disadvantages

ECMO is a good device for acute resuscitation of a patient in shock, as it offers quick placement and resuscitation. But it is falling out of favor because of significant disadvantages.

Its major drawback is that it provides no left ventricular unloading. Although in a very unstable patient ECMO can stabilize end organs and restore their function, the lack of left ventricular unloading and reduced ventricular work threaten the myocardium. It creates extremely high afterload; therefore, in a left ventricle with poor function, wall tension and myocardial oxygen demand increase. Multiple studies have shown that coronary perfusion worsens, especially if the patient is cannulated peripherally. Because relative cerebral hypoxia occurs in many situations, it is imperative to check blood saturations at multiple sites to determine if perfusion is adequate everywhere.    

Ineffective left ventricular unloading with venoarterial ECMO is managed in several ways. Sometimes left ventricular distention is slight and the effects are subtle. Left ventricular distention causing pulmonary edema can be addressed with:

• Inotropes (in moderate doses)
• Anticoagulation to prevent left ventricular thrombus formation
• An intra-aortic balloon pump. Most patients on ECMO already have an intra-aortic balloon pump in place, and it should be left in to provide additional support. For those who do not have one, it should be placed via the contralateral femoral artery.

If problems persist despite these measures, apical cannulation or left ventricular septostomy can be performed.

Outcomes with ECMO have been disappointing. Studies show that whether ECMO was indicated for cardiac failure or for respiratory failure, survival is only about 25% at 5 years. Analyzing data only for arteriovenous ECMO, survival was 48% in bridged patients and 41% in patients who were weaned.

The Extracorporeal Life Support Organization Registry, in their international summary from 2010, found that 34% of cardiac patients on ECMO survived to discharge or transfer. Most of these patients had cardiogenic shock from acute myocardial infarction. Outcomes are so poor because of complications endemic to ECMO, eg, dialysis-dependent renal failure (about 40%) and neurologic complications (about 30%), often involving ischemic or hemorrhagic stroke.

Limb and pump complications were also significant in the past. These have been reduced with the new reperfusion cannula and the Quadrox oxygenator.  

Complications unique to ECMO should be understood and anticipated so that they can be avoided. Better tools are available, ie, Impella and TandemHeart.

Left-sided Impella: A longer-term temporary support

ECMO is a temporary fix that is usually used only for a few days. If longer support is needed, axillary placement of an Impella should be used as a bridge to recovery, transplant, or a durable LVAD.

The Impella device (Figure 3) is a miniature rotary blood pump increasingly used to treat cardiogenic shock. It is inserted retrograde across the aortic valve to provide short-term ventricular support. Most devices are approved by the US Food and Drug Administration (FDA) for less than 7 days of use, but we have experience using them up to 30 days. They are very hemocompatible, involving minimal hemolysis. Axillary placement allows early extubation and ambulation and is more stable than groin placement.

Several models are available: the 2.5 and 3.5 L/min devices can be placed percutaneously, while the 5 L/min model must be surgically placed in the axillary or groin region. Heparin is required with their use. They can replace ECMO. A right ventricular assist device (RVAD), Impella RP, is also available.

Physiologic impact of the Impella

The Impella fully unloads the left ventricle, reducing myocardial oxygen demand and increasing myocardial blood flow. It reduces end-diastolic volume and pressure, the mechanical work of the heart, and wall tension. Microvascular resistance is reduced, allowing increased coronary flow. Cardiac output and power are increased by multiple means.^8–11

The RECOVER 1 trial evaluated the 5L Impella placed after cardiac surgery. The cardiac index increased in all the patients, and the systemic vascular resistance and wedge pressure decreased.¹²

Unloading the ventricle is critical. Meyns  and colleagues¹³ found a fivefold reduction in infarct size from baseline in a left anterior descending occlusion model in pigs after off-loading the ventricle.

Impella has the advantage of simple percutaneous insertion (the 2.5 and CP models). It also tests right ventricular tolerance: if the right ventricle is doing well, one can predict with high certainty that it will tolerate an LVAD (eg, HeartWare, HeartMate 2 (Pleasanton, CA), or HeartMate 3 when available).

Disadvantages include that it provides only left ventricular support, although a right ventricular device can be inserted for dual support. Placement requires fluoroscopic or echocardiographic guidance.

TandemHeart requires septal puncture

The TandemHeart is approved for short-term and biventricular use. It consists of an extracorporeal centrifugal pump that withdraws blood from the left atrium via a trans-septal cannula placed through the femoral vein (Figure 4) and returns it to one or both femoral arteries. The blood is pumped at up to 5 L/min.

It is designed to reduce the pulmonary capillary wedge pressure, ventricular work, and myocardial oxygen demand and increase cardiac output and mean arterial pressure. It has the advantages of percutaneous placement and the ability to provide biventricular support with 2 devices. It can be used for up to 3 weeks. It can easily be converted to ECMO by either splicing in an oxygenator or adding another cannula.

Although the TandemHeart provides significant support, it is no longer often used. A 21F venous cannula must be passed to the left atrium by trans-septal puncture, which requires advanced skill and must be done in the catheterization laboratory. Insertion can take too much time and cause bleeding in patients taking an anticoagulant. Insertion usually destroys the septum, and removal requires a complete patch of the entire septum. Systemic anticoagulation is required. Other disadvantages are risks of hemolysis, limb ischemia, and infection with longer support times.

The CentriMag (Levitronix LLC; Framingham, MA) is an improved device that requires only 1 cannula instead of 2 to cover both areas.

DEVICES FOR RIGHT-SIDED SUPPORT

Most early devices were designed for left-sided support. The right heart, especially in failure, has been more difficult to manage. Previously the only option for a patient with right ventricular failure was venoarterial ECMO. This is more support than needed for a patient with isolated right ventricular failure and involves the risk of multiple complications from the device.

With more options available for the right heart (Table 3), we can choose the most appropriate device according to the underlying cause of right heart failure (eg, right ventricular infarct, pulmonary hypertension), the likelihood of recovery, and the expected time to recovery.

The ideal RVAD would be easy to implant, maintain, and remove. It would allow for chest closure and patient ambulation. It would be durable and biocompatible, so that it could remain implanted for months if necessary. It would cause little blood trauma, have the capability for adding an oxygenator for pulmonary support, and be cost-effective.

Although no single system has all these qualities, each available device fulfills certain combinations of these criteria, so the best one can be selected for each patient’s needs.

ECMO Rotaflow centrifugal pump: Fast, simple, inexpensive

A recent improvement to ECMO is the Rotaflow centrifugal pump (Maquet, Wayne, NJ), which is connected by sewing an 8-mm graft onto the pulmonary artery and placing a venous cannula in the femoral vein. If the patient is not bleeding, the chest can then be closed. This creates a fast, simple, and inexpensive temporary RVAD system. When the patient is ready to be weaned, the outflow graft can be disconnected at the bedside without reopening the chest.

The disadvantage is that the Rotaflow system contains a sapphire bearing. Although it is magnetically coupled, it generates heat and is a nidus for thrombus formation, which can lead to pump failure and embolization. This system can be used for patients who are expected to need support for less than 5 to 7 days. Beyond this duration, the incidence of complications increases. 

CentriMag Ventricular Assist System offers right, left, or bilateral support

The CentriMag Ventricular Assist System is a fully magnetically levitated pump containing no bearings or seals, and with the same technology as is found in many of the durable devices such as HeartMate 3. It is coupled with a reusable motor and is easy to use.

CentriMag offers versatility, allowing for right, left, or bilateral ventricular support. An oxygenator can be added for pulmonary edema and additional support. It is the most biocompatible device and is FDA-approved for use for 4 weeks, although it has been used successfully for much longer. It allows for chest closure and ambulation. It is especially important as a bridge to transplant. The main disadvantage is that insertion and removal require sternotomy.

Impella RP: One size does not fit all

The Impella RP (Figure 5) has an 11F catheter diameter, 23F pump, and a maximum flow rate of more than 4 L/minute. It has a unique 3-dimensional cannula design based on computed tomography 3-dimensional reconstructions from hundreds of patients.

The device is biocompatible and can be used for support for more than 7 days, although most patients require only 3 or 4 days. There is almost no priming volume, so there is no hemodilution.

The disadvantages are that it is more challenging to place than other devices, and some patients cannot use it because the cannula does not fit. It also does not provide pulmonary support. Finally, it is the most expensive of the 3 right-sided devices.

CASE REVISITED

The patient described at the beginning of this article was extubated on day 12 but was then reintubated. On day 20, a tracheotomy tube was placed. By day 24, he had improved so little that his family signed a “do-not-resuscitate–comfort-care-arrest” order (ie, if the patient’s heart or breathing stops, only comfort care is to be provided).

But slowly he got better, and the Impella was removed on day 30. Afterward, serum creatinine and liver function tests began rising again, requiring dobutamine for heart support.

On day 34, his family reversed the do-not-resuscitate order, and he was reevaluated for an LVAD as destination therapy. At this point, echocardiography showed a left ventricular ejection fraction of 10%, normal right ventricular function, with a normal heartbeat and valves. On day 47, a HeartMate II LVAD was placed.

On postoperative day 18, he was transferred out of the intensive care unit, then discharged to an acute rehabilitation facility 8 days later (hospital day 73). He was subsequently discharged.

At a recent follow-up appointment, the patient said that he was feeling “pretty good” and walked with no shortness of breath.

A 43-year-old man presented to a community hospital with acute chest pain and shortness of breath and was diagnosed with anterior ST-elevation myocardial infarction. He was a smoker with a history of alcohol abuse, hypertension, and hyperlipidemia, and in the past he had undergone percutaneous coronary interventions to the right coronary artery and the first obtuse marginal artery.

Angiography showed total occlusion in the left anterior descending artery, 90% stenosis in the right coronary artery, and mild disease in the left circumflex artery. A drug-eluting stent was placed in the left anterior descending artery, resulting in good blood flow. 

However, his left ventricle continued to have severe dysfunction. An intra-aortic balloon pump was inserted. Afterward, computed tomography showed subsegmental pulmonary embolism with congestion. His mean arterial pressure was 60 mm Hg (normal 70–110), central venous pressure 12 mm Hg (3–8), pulmonary artery pressure 38/26 mm Hg (15–30/4–12), pulmonary capillary wedge pressure 24 mm Hg (2–15), and cardiac index 1.4 L/min (2.5–4).

The patient was started on dobutamine and norepinephrine and transferred to Cleveland Clinic on day 2. Over the next day, he had runs of ventricular tachycardia, for which he was given amiodarone and lidocaine. His urine output was low, and his serum creatinine was elevated at 1.65 mg/dL (baseline 1.2, normal 0.5–1.5). Liver function tests were also elevated, with aspartate aminotransferase at 115 U/L(14–40) and alanine aminotransferase at 187 U/L (10–54).

Poor oxygenation was evident: his arterial partial pressure of oxygen was 64 mm Hg (normal 75–100). He was intubated and given 100% oxygen with positive end-expiratory pressure of 12 cm H₂O.

Echocardiography showed a left ventricular ejection fraction of 15% (normal 55%–70%) and mild right ventricular dysfunction.

ECMO and then Impella placement

On his third hospital day, a venoarterial extracorporeal membrane oxygenation (ECMO) device was placed peripherally (Figure 1).

His hemodynamic variables stabilized, and he was weaned off dobutamine and norepinephrine. Results of liver function tests normalized, his urinary output increased, and his serum creatinine dropped to a normal 1.0 mg/dL. However, a chest radiograph showed pulmonary congestion, and echocardiography now showed severe left ventricular dysfunction.

On hospital day 5, the patient underwent surgical placement of an Impella 5.0 device (Abiomed, Danvers, MA) through the right axillary artery in an effort to improve his pulmonary edema. The ECMO device was removed. Placement of a venovenous ECMO device was deemed unnecessary when oxygenation improved with the Impella.

Three days after Impella placement, radiography showed improved edema with some remaining pleural effusion.

ACUTE CARDIOGENIC SHOCK

Cardiogenic shock remains a challenging clinical problem: patients with it are among the sickest in the hospital, and many of them die. ECMO was once the only therapy available and is still widely used. However, it is a 2-edged sword; complications such as bleeding, infection, and thrombosis are almost inevitable if it is used for long. Importantly, patients are usually kept intubated and bedridden.

In recent years, new devices have become available that are easier to place (some in the catheterization laboratory or even at the bedside) and allow safer bridging to recovery, transplant, or other therapies.

This case illustrates the natural history of cardiogenic shock and the preferred clinical approach: ie, ongoing evaluation that permits rapid response to evolving challenges.

In general, acute cardiogenic shock occurs within 24 to 48 hours after the initial insult, so even if a procedure succeeds, the patient may develop progressive hypotension and organ dysfunction. Reduced cardiac output causes a downward spiral with multiple systemic and inflammatory processes as well as increased nitric oxide synthesis, leading to progressive decline and eventual end-organ dysfunction.

Continuously evaluate

The cardiac team should continuously assess the acuity and severity of a patient’s condition, with the goals of maintaining end-organ perfusion and identifying the source of problems. Refractory cardiogenic shock, with tissue hypoperfusion despite vasoactive medications and treatment of the underlying cause, is associated with in-hospital mortality rates ranging from 30% to 50%.^1,2 The rates have actually increased over the past decade, as sicker patients are being treated.

When a patient presents with cardiogenic shock, we first try a series of vasoactive drugs and usually an intra-aortic balloon pump (Figure 2). We then tailor treatment depending on etiology. For example, a patient may have viral myocarditis and may even require a biopsy.

If cardiogenic shock is refractory, mechanical circulatory support devices can be a short-term bridge to either recovery or a new decision. A multidisciplinary team should be consulted to consider transplant, a long-term device, or palliative care. Sometimes a case requires “bridging to a bridge,” with several devices used short-term in turn.

Prognostic factors in cardiogenic shock

Several tools help predict outcome in a severely ill patient. End-organ function, indicated by blood lactate levels and estimated glomerular filtration rate, is perhaps the most informative and should be monitored serially.

CardShock³ is a simple scoring system based on age, mental status at presentation, laboratory values, and medical history. Patients receive 1 point for each of the following factors:

• Age > 75
• Confusion at presentation
• Previous myocardial infarction or coronary artery bypass grafting
• Acute coronary syndrome etiology
• Left ventricular ejection fraction < 40%
• Blood lactate level between 2 and 4 mmol/L, inclusively (2 points for lactate levels > 4 mmol/L)
• Estimated glomerular filtration rate between 30 and 60 mL/min/1.73 m², inclusively (2 points if < 30 mL/min/1.73 m²). 

Thus, scores range from 0 (best) to 9 (worst). A score of 0 to 3 points was associated with a 9% risk of death in the hospital, a score of 4 or 5 with a risk of 36%, and a score of 6 through 9 with a risk of 77%.³

The Survival After Veno-arterial ECMO (SAVE) score (www.save-score.com) is a prediction tool derived from a large international ECMO registry.⁴ It is based on patient age, diagnosis, and indicators of end-organ dysfunction. Scores range from –35 (worst) to +7 (best).

The mortality rate associated with postcardiotomy cardiogenic shock increases with the amount of inotropic support provided. In a 1996–1999 case series of patients who underwent open-heart surgery,⁵ the hospital mortality rate was 40% in those who received 2 inotropes in high doses and 80% in those who received 3. A strategy of early implementation of mechanical support is critical.

Selection criteria for destination therapy

Deciding whether a patient should receive a long-term device is frequently a challenge. The decision often must be based on limited information about not only the medical indications but also psychosocial factors that influence long-term success.

The Centers for Medicare and Medicaid Services have established criteria for candidates for left ventricular assist devices (LVADs) as destination therapy.⁶ Contraindications established for heart transplant should also be considered (Table 1).

CASE REVISITED

Several factors argued against LVAD placement in our patient. He had no health insurance and had been off medications. He smoked and said he consumed 3 hard liquor drinks per week. His Stanford Integrated Psychosocial Assessment for Transplantation score was 30 (minimally acceptable). He had hypoxia with subsegmental pulmonary edema, a strong contraindication to immediate transplant.

On the other hand, he had only mild right ventricular dysfunction. His CardShock score was 4 (intermediate risk, based on lactate 1.5 mmol/L and estimated glomerular filtration rate 52 mL/min/1.73 m²). His SAVE score was –9 (class IV), which overall is associated with a 30% risk of death (low enough to consider treatment).

During the patient’s time on temporary support, the team had the opportunity to better understand him and assess his family support and his ability to handle a permanent device. His surviving the acute course bolstered the team’s confidence that he could enjoy long-term survival with destination therapy.

CATHETERIZATION LABORATORY DEVICE CAPABILITIES

Although most implantation procedures are done in the operating room, they are often done in the catheterization laboratory because patients undergoing catheterization may not be stable enough for transfer, or an emergency intervention may be required during the night. Catheterization interventionists are also an important part of the team to help determine the best approach for long-term therapy.

The catheterization laboratory has multiple acute intervention options. Usually, decisions must be made quickly. In general, patients needing mechanical support are managed as follows:

• Those who need circulation support and oxygenation receive ECMO
• Those who need circulation support alone because of mechanical issues (eg, myocardial infarction) are considered for an intra-aortic balloon pump, Impella, or TandemHeart pump (Cardiac Assist, Pittsburgh, PA).

Factors that guide the selection of a temporary pump include:

• Left ventricular function
• Right ventricular function
• Aortic valve stenosis (some devices cannot be inserted through critical aortic stenosis)
• Aortic regurgitation (can affect some devices)
• Peripheral artery disease (some devices are large and must be placed percutaneously).

CHOOSING AMONG PERCUTANEOUS DEVICES

Circulatory support in cardiogenic shock improves outcomes, and devices play an important role in supporting high-risk procedures. The goal is not necessarily to use the device throughout the hospital stay. Acute stabilization is most important initially; a more considered decision about long-term therapy can be made when more is known about the patient.

Patient selection is the most important component of success. However, randomized data to support outcomes with the various devices are sparse and complicated by the critically ill state of the patient population.

SHORT-TERM CIRCULATORY SUPPORT: ECMO, IMPELLA, TANDEMHEART

A menu of options is available for temporary mechanical support. Options differ by their degree of circulatory support and ease of insertion (Table 2).

ECMO: A fast option with many advantages

ECMO has evolved and now can be placed quickly. A remote diagnostic platform such as CardioHub permits management at the bedside, in the medical unit, or in the cardiac intensive care unit.⁷

ECMO has several advantages. It can be used during cardiopulmonary bypass, it provides oxygenation, it is the only option in the setting of lung injury, it can be placed peripherally (without thoracotomy), and it is the only percutaneous option for biventricular support.

ECMO also has significant disadvantages

ECMO is a good device for acute resuscitation of a patient in shock, as it offers quick placement and resuscitation. But it is falling out of favor because of significant disadvantages.

Its major drawback is that it provides no left ventricular unloading. Although in a very unstable patient ECMO can stabilize end organs and restore their function, the lack of left ventricular unloading and reduced ventricular work threaten the myocardium. It creates extremely high afterload; therefore, in a left ventricle with poor function, wall tension and myocardial oxygen demand increase. Multiple studies have shown that coronary perfusion worsens, especially if the patient is cannulated peripherally. Because relative cerebral hypoxia occurs in many situations, it is imperative to check blood saturations at multiple sites to determine if perfusion is adequate everywhere.    

Ineffective left ventricular unloading with venoarterial ECMO is managed in several ways. Sometimes left ventricular distention is slight and the effects are subtle. Left ventricular distention causing pulmonary edema can be addressed with:

• Inotropes (in moderate doses)
• Anticoagulation to prevent left ventricular thrombus formation
• An intra-aortic balloon pump. Most patients on ECMO already have an intra-aortic balloon pump in place, and it should be left in to provide additional support. For those who do not have one, it should be placed via the contralateral femoral artery.

If problems persist despite these measures, apical cannulation or left ventricular septostomy can be performed.

Outcomes with ECMO have been disappointing. Studies show that whether ECMO was indicated for cardiac failure or for respiratory failure, survival is only about 25% at 5 years. Analyzing data only for arteriovenous ECMO, survival was 48% in bridged patients and 41% in patients who were weaned.

The Extracorporeal Life Support Organization Registry, in their international summary from 2010, found that 34% of cardiac patients on ECMO survived to discharge or transfer. Most of these patients had cardiogenic shock from acute myocardial infarction. Outcomes are so poor because of complications endemic to ECMO, eg, dialysis-dependent renal failure (about 40%) and neurologic complications (about 30%), often involving ischemic or hemorrhagic stroke.

Limb and pump complications were also significant in the past. These have been reduced with the new reperfusion cannula and the Quadrox oxygenator.  

Complications unique to ECMO should be understood and anticipated so that they can be avoided. Better tools are available, ie, Impella and TandemHeart.

Left-sided Impella: A longer-term temporary support

ECMO is a temporary fix that is usually used only for a few days. If longer support is needed, axillary placement of an Impella should be used as a bridge to recovery, transplant, or a durable LVAD.

The Impella device (Figure 3) is a miniature rotary blood pump increasingly used to treat cardiogenic shock. It is inserted retrograde across the aortic valve to provide short-term ventricular support. Most devices are approved by the US Food and Drug Administration (FDA) for less than 7 days of use, but we have experience using them up to 30 days. They are very hemocompatible, involving minimal hemolysis. Axillary placement allows early extubation and ambulation and is more stable than groin placement.

Several models are available: the 2.5 and 3.5 L/min devices can be placed percutaneously, while the 5 L/min model must be surgically placed in the axillary or groin region. Heparin is required with their use. They can replace ECMO. A right ventricular assist device (RVAD), Impella RP, is also available.

Physiologic impact of the Impella

The Impella fully unloads the left ventricle, reducing myocardial oxygen demand and increasing myocardial blood flow. It reduces end-diastolic volume and pressure, the mechanical work of the heart, and wall tension. Microvascular resistance is reduced, allowing increased coronary flow. Cardiac output and power are increased by multiple means.^8–11

The RECOVER 1 trial evaluated the 5L Impella placed after cardiac surgery. The cardiac index increased in all the patients, and the systemic vascular resistance and wedge pressure decreased.¹²

Unloading the ventricle is critical. Meyns  and colleagues¹³ found a fivefold reduction in infarct size from baseline in a left anterior descending occlusion model in pigs after off-loading the ventricle.

Impella has the advantage of simple percutaneous insertion (the 2.5 and CP models). It also tests right ventricular tolerance: if the right ventricle is doing well, one can predict with high certainty that it will tolerate an LVAD (eg, HeartWare, HeartMate 2 (Pleasanton, CA), or HeartMate 3 when available).

Disadvantages include that it provides only left ventricular support, although a right ventricular device can be inserted for dual support. Placement requires fluoroscopic or echocardiographic guidance.

TandemHeart requires septal puncture

The TandemHeart is approved for short-term and biventricular use. It consists of an extracorporeal centrifugal pump that withdraws blood from the left atrium via a trans-septal cannula placed through the femoral vein (Figure 4) and returns it to one or both femoral arteries. The blood is pumped at up to 5 L/min.

It is designed to reduce the pulmonary capillary wedge pressure, ventricular work, and myocardial oxygen demand and increase cardiac output and mean arterial pressure. It has the advantages of percutaneous placement and the ability to provide biventricular support with 2 devices. It can be used for up to 3 weeks. It can easily be converted to ECMO by either splicing in an oxygenator or adding another cannula.

Although the TandemHeart provides significant support, it is no longer often used. A 21F venous cannula must be passed to the left atrium by trans-septal puncture, which requires advanced skill and must be done in the catheterization laboratory. Insertion can take too much time and cause bleeding in patients taking an anticoagulant. Insertion usually destroys the septum, and removal requires a complete patch of the entire septum. Systemic anticoagulation is required. Other disadvantages are risks of hemolysis, limb ischemia, and infection with longer support times.

The CentriMag (Levitronix LLC; Framingham, MA) is an improved device that requires only 1 cannula instead of 2 to cover both areas.

DEVICES FOR RIGHT-SIDED SUPPORT

Most early devices were designed for left-sided support. The right heart, especially in failure, has been more difficult to manage. Previously the only option for a patient with right ventricular failure was venoarterial ECMO. This is more support than needed for a patient with isolated right ventricular failure and involves the risk of multiple complications from the device.

With more options available for the right heart (Table 3), we can choose the most appropriate device according to the underlying cause of right heart failure (eg, right ventricular infarct, pulmonary hypertension), the likelihood of recovery, and the expected time to recovery.

The ideal RVAD would be easy to implant, maintain, and remove. It would allow for chest closure and patient ambulation. It would be durable and biocompatible, so that it could remain implanted for months if necessary. It would cause little blood trauma, have the capability for adding an oxygenator for pulmonary support, and be cost-effective.

Although no single system has all these qualities, each available device fulfills certain combinations of these criteria, so the best one can be selected for each patient’s needs.

ECMO Rotaflow centrifugal pump: Fast, simple, inexpensive

A recent improvement to ECMO is the Rotaflow centrifugal pump (Maquet, Wayne, NJ), which is connected by sewing an 8-mm graft onto the pulmonary artery and placing a venous cannula in the femoral vein. If the patient is not bleeding, the chest can then be closed. This creates a fast, simple, and inexpensive temporary RVAD system. When the patient is ready to be weaned, the outflow graft can be disconnected at the bedside without reopening the chest.

The disadvantage is that the Rotaflow system contains a sapphire bearing. Although it is magnetically coupled, it generates heat and is a nidus for thrombus formation, which can lead to pump failure and embolization. This system can be used for patients who are expected to need support for less than 5 to 7 days. Beyond this duration, the incidence of complications increases. 

CentriMag Ventricular Assist System offers right, left, or bilateral support

The CentriMag Ventricular Assist System is a fully magnetically levitated pump containing no bearings or seals, and with the same technology as is found in many of the durable devices such as HeartMate 3. It is coupled with a reusable motor and is easy to use.

CentriMag offers versatility, allowing for right, left, or bilateral ventricular support. An oxygenator can be added for pulmonary edema and additional support. It is the most biocompatible device and is FDA-approved for use for 4 weeks, although it has been used successfully for much longer. It allows for chest closure and ambulation. It is especially important as a bridge to transplant. The main disadvantage is that insertion and removal require sternotomy.

Impella RP: One size does not fit all

The Impella RP (Figure 5) has an 11F catheter diameter, 23F pump, and a maximum flow rate of more than 4 L/minute. It has a unique 3-dimensional cannula design based on computed tomography 3-dimensional reconstructions from hundreds of patients.

The device is biocompatible and can be used for support for more than 7 days, although most patients require only 3 or 4 days. There is almost no priming volume, so there is no hemodilution.

The disadvantages are that it is more challenging to place than other devices, and some patients cannot use it because the cannula does not fit. It also does not provide pulmonary support. Finally, it is the most expensive of the 3 right-sided devices.

CASE REVISITED

The patient described at the beginning of this article was extubated on day 12 but was then reintubated. On day 20, a tracheotomy tube was placed. By day 24, he had improved so little that his family signed a “do-not-resuscitate–comfort-care-arrest” order (ie, if the patient’s heart or breathing stops, only comfort care is to be provided).

But slowly he got better, and the Impella was removed on day 30. Afterward, serum creatinine and liver function tests began rising again, requiring dobutamine for heart support.

On day 34, his family reversed the do-not-resuscitate order, and he was reevaluated for an LVAD as destination therapy. At this point, echocardiography showed a left ventricular ejection fraction of 10%, normal right ventricular function, with a normal heartbeat and valves. On day 47, a HeartMate II LVAD was placed.

On postoperative day 18, he was transferred out of the intensive care unit, then discharged to an acute rehabilitation facility 8 days later (hospital day 73). He was subsequently discharged.

At a recent follow-up appointment, the patient said that he was feeling “pretty good” and walked with no shortness of breath.

A 43-year-old man presented to a community hospital with acute chest pain and shortness of breath and was diagnosed with anterior ST-elevation myocardial infarction. He was a smoker with a history of alcohol abuse, hypertension, and hyperlipidemia, and in the past he had undergone percutaneous coronary interventions to the right coronary artery and the first obtuse marginal artery.

Angiography showed total occlusion in the left anterior descending artery, 90% stenosis in the right coronary artery, and mild disease in the left circumflex artery. A drug-eluting stent was placed in the left anterior descending artery, resulting in good blood flow. 

However, his left ventricle continued to have severe dysfunction. An intra-aortic balloon pump was inserted. Afterward, computed tomography showed subsegmental pulmonary embolism with congestion. His mean arterial pressure was 60 mm Hg (normal 70–110), central venous pressure 12 mm Hg (3–8), pulmonary artery pressure 38/26 mm Hg (15–30/4–12), pulmonary capillary wedge pressure 24 mm Hg (2–15), and cardiac index 1.4 L/min (2.5–4).

The patient was started on dobutamine and norepinephrine and transferred to Cleveland Clinic on day 2. Over the next day, he had runs of ventricular tachycardia, for which he was given amiodarone and lidocaine. His urine output was low, and his serum creatinine was elevated at 1.65 mg/dL (baseline 1.2, normal 0.5–1.5). Liver function tests were also elevated, with aspartate aminotransferase at 115 U/L(14–40) and alanine aminotransferase at 187 U/L (10–54).

Poor oxygenation was evident: his arterial partial pressure of oxygen was 64 mm Hg (normal 75–100). He was intubated and given 100% oxygen with positive end-expiratory pressure of 12 cm H₂O.

Echocardiography showed a left ventricular ejection fraction of 15% (normal 55%–70%) and mild right ventricular dysfunction.

ECMO and then Impella placement

On his third hospital day, a venoarterial extracorporeal membrane oxygenation (ECMO) device was placed peripherally (Figure 1).

His hemodynamic variables stabilized, and he was weaned off dobutamine and norepinephrine. Results of liver function tests normalized, his urinary output increased, and his serum creatinine dropped to a normal 1.0 mg/dL. However, a chest radiograph showed pulmonary congestion, and echocardiography now showed severe left ventricular dysfunction.

On hospital day 5, the patient underwent surgical placement of an Impella 5.0 device (Abiomed, Danvers, MA) through the right axillary artery in an effort to improve his pulmonary edema. The ECMO device was removed. Placement of a venovenous ECMO device was deemed unnecessary when oxygenation improved with the Impella.

Three days after Impella placement, radiography showed improved edema with some remaining pleural effusion.

ACUTE CARDIOGENIC SHOCK

Cardiogenic shock remains a challenging clinical problem: patients with it are among the sickest in the hospital, and many of them die. ECMO was once the only therapy available and is still widely used. However, it is a 2-edged sword; complications such as bleeding, infection, and thrombosis are almost inevitable if it is used for long. Importantly, patients are usually kept intubated and bedridden.

In recent years, new devices have become available that are easier to place (some in the catheterization laboratory or even at the bedside) and allow safer bridging to recovery, transplant, or other therapies.

This case illustrates the natural history of cardiogenic shock and the preferred clinical approach: ie, ongoing evaluation that permits rapid response to evolving challenges.

In general, acute cardiogenic shock occurs within 24 to 48 hours after the initial insult, so even if a procedure succeeds, the patient may develop progressive hypotension and organ dysfunction. Reduced cardiac output causes a downward spiral with multiple systemic and inflammatory processes as well as increased nitric oxide synthesis, leading to progressive decline and eventual end-organ dysfunction.

Continuously evaluate

The cardiac team should continuously assess the acuity and severity of a patient’s condition, with the goals of maintaining end-organ perfusion and identifying the source of problems. Refractory cardiogenic shock, with tissue hypoperfusion despite vasoactive medications and treatment of the underlying cause, is associated with in-hospital mortality rates ranging from 30% to 50%.^1,2 The rates have actually increased over the past decade, as sicker patients are being treated.

When a patient presents with cardiogenic shock, we first try a series of vasoactive drugs and usually an intra-aortic balloon pump (Figure 2). We then tailor treatment depending on etiology. For example, a patient may have viral myocarditis and may even require a biopsy.

If cardiogenic shock is refractory, mechanical circulatory support devices can be a short-term bridge to either recovery or a new decision. A multidisciplinary team should be consulted to consider transplant, a long-term device, or palliative care. Sometimes a case requires “bridging to a bridge,” with several devices used short-term in turn.

Prognostic factors in cardiogenic shock

Several tools help predict outcome in a severely ill patient. End-organ function, indicated by blood lactate levels and estimated glomerular filtration rate, is perhaps the most informative and should be monitored serially.

CardShock³ is a simple scoring system based on age, mental status at presentation, laboratory values, and medical history. Patients receive 1 point for each of the following factors:

• Age > 75
• Confusion at presentation
• Previous myocardial infarction or coronary artery bypass grafting
• Acute coronary syndrome etiology
• Left ventricular ejection fraction < 40%
• Blood lactate level between 2 and 4 mmol/L, inclusively (2 points for lactate levels > 4 mmol/L)
• Estimated glomerular filtration rate between 30 and 60 mL/min/1.73 m², inclusively (2 points if < 30 mL/min/1.73 m²). 

Thus, scores range from 0 (best) to 9 (worst). A score of 0 to 3 points was associated with a 9% risk of death in the hospital, a score of 4 or 5 with a risk of 36%, and a score of 6 through 9 with a risk of 77%.³

The Survival After Veno-arterial ECMO (SAVE) score (www.save-score.com) is a prediction tool derived from a large international ECMO registry.⁴ It is based on patient age, diagnosis, and indicators of end-organ dysfunction. Scores range from –35 (worst) to +7 (best).

The mortality rate associated with postcardiotomy cardiogenic shock increases with the amount of inotropic support provided. In a 1996–1999 case series of patients who underwent open-heart surgery,⁵ the hospital mortality rate was 40% in those who received 2 inotropes in high doses and 80% in those who received 3. A strategy of early implementation of mechanical support is critical.

Selection criteria for destination therapy

Deciding whether a patient should receive a long-term device is frequently a challenge. The decision often must be based on limited information about not only the medical indications but also psychosocial factors that influence long-term success.

The Centers for Medicare and Medicaid Services have established criteria for candidates for left ventricular assist devices (LVADs) as destination therapy.⁶ Contraindications established for heart transplant should also be considered (Table 1).

CASE REVISITED

Several factors argued against LVAD placement in our patient. He had no health insurance and had been off medications. He smoked and said he consumed 3 hard liquor drinks per week. His Stanford Integrated Psychosocial Assessment for Transplantation score was 30 (minimally acceptable). He had hypoxia with subsegmental pulmonary edema, a strong contraindication to immediate transplant.

On the other hand, he had only mild right ventricular dysfunction. His CardShock score was 4 (intermediate risk, based on lactate 1.5 mmol/L and estimated glomerular filtration rate 52 mL/min/1.73 m²). His SAVE score was –9 (class IV), which overall is associated with a 30% risk of death (low enough to consider treatment).

During the patient’s time on temporary support, the team had the opportunity to better understand him and assess his family support and his ability to handle a permanent device. His surviving the acute course bolstered the team’s confidence that he could enjoy long-term survival with destination therapy.

CATHETERIZATION LABORATORY DEVICE CAPABILITIES

Although most implantation procedures are done in the operating room, they are often done in the catheterization laboratory because patients undergoing catheterization may not be stable enough for transfer, or an emergency intervention may be required during the night. Catheterization interventionists are also an important part of the team to help determine the best approach for long-term therapy.

The catheterization laboratory has multiple acute intervention options. Usually, decisions must be made quickly. In general, patients needing mechanical support are managed as follows:

• Those who need circulation support and oxygenation receive ECMO
• Those who need circulation support alone because of mechanical issues (eg, myocardial infarction) are considered for an intra-aortic balloon pump, Impella, or TandemHeart pump (Cardiac Assist, Pittsburgh, PA).

Factors that guide the selection of a temporary pump include:

• Left ventricular function
• Right ventricular function
• Aortic valve stenosis (some devices cannot be inserted through critical aortic stenosis)
• Aortic regurgitation (can affect some devices)
• Peripheral artery disease (some devices are large and must be placed percutaneously).

CHOOSING AMONG PERCUTANEOUS DEVICES

Circulatory support in cardiogenic shock improves outcomes, and devices play an important role in supporting high-risk procedures. The goal is not necessarily to use the device throughout the hospital stay. Acute stabilization is most important initially; a more considered decision about long-term therapy can be made when more is known about the patient.

Patient selection is the most important component of success. However, randomized data to support outcomes with the various devices are sparse and complicated by the critically ill state of the patient population.

SHORT-TERM CIRCULATORY SUPPORT: ECMO, IMPELLA, TANDEMHEART

A menu of options is available for temporary mechanical support. Options differ by their degree of circulatory support and ease of insertion (Table 2).

ECMO: A fast option with many advantages

ECMO has evolved and now can be placed quickly. A remote diagnostic platform such as CardioHub permits management at the bedside, in the medical unit, or in the cardiac intensive care unit.⁷

ECMO has several advantages. It can be used during cardiopulmonary bypass, it provides oxygenation, it is the only option in the setting of lung injury, it can be placed peripherally (without thoracotomy), and it is the only percutaneous option for biventricular support.

ECMO also has significant disadvantages

ECMO is a good device for acute resuscitation of a patient in shock, as it offers quick placement and resuscitation. But it is falling out of favor because of significant disadvantages.

Its major drawback is that it provides no left ventricular unloading. Although in a very unstable patient ECMO can stabilize end organs and restore their function, the lack of left ventricular unloading and reduced ventricular work threaten the myocardium. It creates extremely high afterload; therefore, in a left ventricle with poor function, wall tension and myocardial oxygen demand increase. Multiple studies have shown that coronary perfusion worsens, especially if the patient is cannulated peripherally. Because relative cerebral hypoxia occurs in many situations, it is imperative to check blood saturations at multiple sites to determine if perfusion is adequate everywhere.    

Ineffective left ventricular unloading with venoarterial ECMO is managed in several ways. Sometimes left ventricular distention is slight and the effects are subtle. Left ventricular distention causing pulmonary edema can be addressed with:

• Inotropes (in moderate doses)
• Anticoagulation to prevent left ventricular thrombus formation
• An intra-aortic balloon pump. Most patients on ECMO already have an intra-aortic balloon pump in place, and it should be left in to provide additional support. For those who do not have one, it should be placed via the contralateral femoral artery.

If problems persist despite these measures, apical cannulation or left ventricular septostomy can be performed.

Outcomes with ECMO have been disappointing. Studies show that whether ECMO was indicated for cardiac failure or for respiratory failure, survival is only about 25% at 5 years. Analyzing data only for arteriovenous ECMO, survival was 48% in bridged patients and 41% in patients who were weaned.

The Extracorporeal Life Support Organization Registry, in their international summary from 2010, found that 34% of cardiac patients on ECMO survived to discharge or transfer. Most of these patients had cardiogenic shock from acute myocardial infarction. Outcomes are so poor because of complications endemic to ECMO, eg, dialysis-dependent renal failure (about 40%) and neurologic complications (about 30%), often involving ischemic or hemorrhagic stroke.

Limb and pump complications were also significant in the past. These have been reduced with the new reperfusion cannula and the Quadrox oxygenator.  

Complications unique to ECMO should be understood and anticipated so that they can be avoided. Better tools are available, ie, Impella and TandemHeart.

Left-sided Impella: A longer-term temporary support

ECMO is a temporary fix that is usually used only for a few days. If longer support is needed, axillary placement of an Impella should be used as a bridge to recovery, transplant, or a durable LVAD.

The Impella device (Figure 3) is a miniature rotary blood pump increasingly used to treat cardiogenic shock. It is inserted retrograde across the aortic valve to provide short-term ventricular support. Most devices are approved by the US Food and Drug Administration (FDA) for less than 7 days of use, but we have experience using them up to 30 days. They are very hemocompatible, involving minimal hemolysis. Axillary placement allows early extubation and ambulation and is more stable than groin placement.

Several models are available: the 2.5 and 3.5 L/min devices can be placed percutaneously, while the 5 L/min model must be surgically placed in the axillary or groin region. Heparin is required with their use. They can replace ECMO. A right ventricular assist device (RVAD), Impella RP, is also available.

Physiologic impact of the Impella

The Impella fully unloads the left ventricle, reducing myocardial oxygen demand and increasing myocardial blood flow. It reduces end-diastolic volume and pressure, the mechanical work of the heart, and wall tension. Microvascular resistance is reduced, allowing increased coronary flow. Cardiac output and power are increased by multiple means.^8–11

The RECOVER 1 trial evaluated the 5L Impella placed after cardiac surgery. The cardiac index increased in all the patients, and the systemic vascular resistance and wedge pressure decreased.¹²

Unloading the ventricle is critical. Meyns  and colleagues¹³ found a fivefold reduction in infarct size from baseline in a left anterior descending occlusion model in pigs after off-loading the ventricle.

Impella has the advantage of simple percutaneous insertion (the 2.5 and CP models). It also tests right ventricular tolerance: if the right ventricle is doing well, one can predict with high certainty that it will tolerate an LVAD (eg, HeartWare, HeartMate 2 (Pleasanton, CA), or HeartMate 3 when available).

Disadvantages include that it provides only left ventricular support, although a right ventricular device can be inserted for dual support. Placement requires fluoroscopic or echocardiographic guidance.

TandemHeart requires septal puncture

The TandemHeart is approved for short-term and biventricular use. It consists of an extracorporeal centrifugal pump that withdraws blood from the left atrium via a trans-septal cannula placed through the femoral vein (Figure 4) and returns it to one or both femoral arteries. The blood is pumped at up to 5 L/min.

It is designed to reduce the pulmonary capillary wedge pressure, ventricular work, and myocardial oxygen demand and increase cardiac output and mean arterial pressure. It has the advantages of percutaneous placement and the ability to provide biventricular support with 2 devices. It can be used for up to 3 weeks. It can easily be converted to ECMO by either splicing in an oxygenator or adding another cannula.

Although the TandemHeart provides significant support, it is no longer often used. A 21F venous cannula must be passed to the left atrium by trans-septal puncture, which requires advanced skill and must be done in the catheterization laboratory. Insertion can take too much time and cause bleeding in patients taking an anticoagulant. Insertion usually destroys the septum, and removal requires a complete patch of the entire septum. Systemic anticoagulation is required. Other disadvantages are risks of hemolysis, limb ischemia, and infection with longer support times.

The CentriMag (Levitronix LLC; Framingham, MA) is an improved device that requires only 1 cannula instead of 2 to cover both areas.

DEVICES FOR RIGHT-SIDED SUPPORT

Most early devices were designed for left-sided support. The right heart, especially in failure, has been more difficult to manage. Previously the only option for a patient with right ventricular failure was venoarterial ECMO. This is more support than needed for a patient with isolated right ventricular failure and involves the risk of multiple complications from the device.

With more options available for the right heart (Table 3), we can choose the most appropriate device according to the underlying cause of right heart failure (eg, right ventricular infarct, pulmonary hypertension), the likelihood of recovery, and the expected time to recovery.

The ideal RVAD would be easy to implant, maintain, and remove. It would allow for chest closure and patient ambulation. It would be durable and biocompatible, so that it could remain implanted for months if necessary. It would cause little blood trauma, have the capability for adding an oxygenator for pulmonary support, and be cost-effective.

Although no single system has all these qualities, each available device fulfills certain combinations of these criteria, so the best one can be selected for each patient’s needs.

ECMO Rotaflow centrifugal pump: Fast, simple, inexpensive

A recent improvement to ECMO is the Rotaflow centrifugal pump (Maquet, Wayne, NJ), which is connected by sewing an 8-mm graft onto the pulmonary artery and placing a venous cannula in the femoral vein. If the patient is not bleeding, the chest can then be closed. This creates a fast, simple, and inexpensive temporary RVAD system. When the patient is ready to be weaned, the outflow graft can be disconnected at the bedside without reopening the chest.

The disadvantage is that the Rotaflow system contains a sapphire bearing. Although it is magnetically coupled, it generates heat and is a nidus for thrombus formation, which can lead to pump failure and embolization. This system can be used for patients who are expected to need support for less than 5 to 7 days. Beyond this duration, the incidence of complications increases. 

CentriMag Ventricular Assist System offers right, left, or bilateral support

The CentriMag Ventricular Assist System is a fully magnetically levitated pump containing no bearings or seals, and with the same technology as is found in many of the durable devices such as HeartMate 3. It is coupled with a reusable motor and is easy to use.

CentriMag offers versatility, allowing for right, left, or bilateral ventricular support. An oxygenator can be added for pulmonary edema and additional support. It is the most biocompatible device and is FDA-approved for use for 4 weeks, although it has been used successfully for much longer. It allows for chest closure and ambulation. It is especially important as a bridge to transplant. The main disadvantage is that insertion and removal require sternotomy.

Impella RP: One size does not fit all

The Impella RP (Figure 5) has an 11F catheter diameter, 23F pump, and a maximum flow rate of more than 4 L/minute. It has a unique 3-dimensional cannula design based on computed tomography 3-dimensional reconstructions from hundreds of patients.

The device is biocompatible and can be used for support for more than 7 days, although most patients require only 3 or 4 days. There is almost no priming volume, so there is no hemodilution.

The disadvantages are that it is more challenging to place than other devices, and some patients cannot use it because the cannula does not fit. It also does not provide pulmonary support. Finally, it is the most expensive of the 3 right-sided devices.

CASE REVISITED

The patient described at the beginning of this article was extubated on day 12 but was then reintubated. On day 20, a tracheotomy tube was placed. By day 24, he had improved so little that his family signed a “do-not-resuscitate–comfort-care-arrest” order (ie, if the patient’s heart or breathing stops, only comfort care is to be provided).

But slowly he got better, and the Impella was removed on day 30. Afterward, serum creatinine and liver function tests began rising again, requiring dobutamine for heart support.

On day 34, his family reversed the do-not-resuscitate order, and he was reevaluated for an LVAD as destination therapy. At this point, echocardiography showed a left ventricular ejection fraction of 10%, normal right ventricular function, with a normal heartbeat and valves. On day 47, a HeartMate II LVAD was placed.

On postoperative day 18, he was transferred out of the intensive care unit, then discharged to an acute rehabilitation facility 8 days later (hospital day 73). He was subsequently discharged.

At a recent follow-up appointment, the patient said that he was feeling “pretty good” and walked with no shortness of breath.

Carotid artery disease that is asymptomatic poses a dilemma: Should the patient undergo revascularization (surgical carotid endarterectomy or percutaneous stenting) or receive medical therapy alone?

On one hand, because one consequence of carotid atherosclerosis—ischemic stroke—can be devastating or deadly, many physicians and patients would rather “do something,” ie, proceed with surgery. Furthermore, several randomized trials^1–4 found carotid endarterectomy superior to medical therapy.

On the other hand, these trials were conducted in the 1990s. Surgery has improved since then, but so has medical therapy. And if we re-examine the data from the trials in terms of the absolute risk reduction and number needed to treat, as opposed to the relative risk reduction, surgery may appear less beneficial.

Needed is a way to identify patients who would benefit from surgery and those who would more likely be harmed. Research in that direction is ongoing.

Here, we present a simple algorithmic approach to managing asymptomatic carotid artery stenosis based on the patient’s age, sex, and life expectancy. Our approach is based on a review of the best available evidence.

UP TO 8% OF ADULTS HAVE STENOSIS

Stroke is the third largest cause of death in the United States and the leading cause of disability.⁵ From 10% to 15% of strokes are associated with carotid artery stenosis.^6,7

The prevalence of asymptomatic carotid disease, defined as stenosis greater than 50%, ranges from 4% to 8% in adults.⁸

However, major societies recommend against screening for carotid stenosis in the general population.^9–12 Similarly, the US Preventive Services Task Force also discourages the use of carotid auscultation as screening in the general population (Table 1).¹³ Generally, cases of asymptomatic carotid stenosis are diagnosed by ultrasonography after the patient’s physician happens to hear a bruit during a routine examination, during a preoperative assessment, or after the patient suffers a transient ischemic attack or stroke on the contralateral side.

CLASS II RECOMMENDATIONS FOR SURGERY OR STENTING

There are well-established guidelines for managing symptomatic carotid disease,¹⁴ based on evidence from the North American Symptomatic Carotid Endarterectomy Trial¹⁵ and the European Carotid Surgery Trial,¹⁶ both from 1998. But how to manage asymptomatic carotid disease remains uncertain.

If stenosis of the internal carotid artery is greater than 70% on ultrasonography, computed tomography, or magnetic resonance imaging, and if the risk of perioperative stroke and death is low (< 3%), current guidelines¹⁴ give carotid endarterectomy a class IIa recommendation (ie, evidence is conflicting, but the weight of evidence is in favor), and they give prophylactic carotid artery stenting with optimal medical treatment a class IIb recommendation (efficacy is less well established).⁵

But medical management has improved, and new data suggest that this improvement may override the minimal net benefit of intervention in some patients.¹⁷ Some authors suggest that it is best to use patient characteristics and imaging features to guide treatment.¹⁸

EVIDENCE TO SUPPORT CAROTID REVASCULARIZATION

Three major trials (Table 2) published nearly 20 years ago provide the foundation of the current guidelines:

• the Endarterectomy for Asymptomatic Carotid Atherosclerosis Study (ACAS)¹
• the Asymptomatic Carotid Surgery Trial (ACST)^2,3
• the Veterans Affairs (VA) Cooperative Study.⁴

A Cochrane review of these trials,¹⁹ where medical therapy consisted only of aspirin and little use of statin therapy, found that carotid endarterectomy reduced the rate of perioperative stroke or death or any subsequent stroke in the next 3 years by 31% (relative risk 69%, 95% confidence interval [CI] 0.57–0.83). “Perioperative” was defined as the period from randomization until 30 days after surgery in the surgical group and an equivalent period in the medical group.

Moreover, carotid endarterectomy reduced the rate of disabling or fatal nonperioperative stroke by 50% compared with medical management alone.^1,2,19 Patients who had contralateral symptomatic disease or who had undergone contralateral carotid endarterectomy seemed to benefit more from the procedure than those who had not.¹⁹

Also, the ACST investigators found that revascularization was associated with a reduction in contralateral strokes (which occurred in 39 vs 64 patients, P = .01) independent of contralateral symptoms or contralateral carotid endarterectomy.^2,3 The exact mechanism is unknown but could be related to better blood pressure control and risk factor modification after carotid endarterectomy.

Another factor supporting revascularization is that the outcomes of revascularization have improved over time. In 2010, the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)²⁰ reported a 30-day periprocedural incidence of death or stroke of only 1.4%, compared with 2.9% in the earlier landmark trials.

Stenting is a noninferior alternative

For patients who have asymptomatic stenosis greater than 80% on color duplex ultrasonography and a risk of stroke or death during carotid endarterectomy that is prohibitively high (> 3%), carotid stenting has proved to be a noninferior alternative.^21,22

The Stenting and Angioplasty With Protection of Patients With High Risk for Endarterectomy (SAPPHIRE) trial²¹ reported a risk of death, stroke, or myocardial infarction of about 5% at 30 days and 10% at 1 year after stenting. A recent observational study revealed lower perioperative complication rates, with a risk of death or stroke of about 3%, which satisfy current guideline requirements.²³

To be deemed at high surgical risk and therefore eligible for the SAPPHIRE trial,²¹ patients had to have clinically significant cardiac disease, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal-nerve palsy, recurrent stenosis after carotid endarterectomy, previous radical neck surgery or radiation therapy to the neck, or age greater than 80.

EVIDENCE AGAINST CAROTID REVASCULARIZATION

Although carotid revascularization has evidence to support it, further interpretation of the data may lessen its apparent benefits.

Small absolute benefit, high number needed to treat

If we compare the relative risk reduction for the outcome of perioperative death or any stroke over 5 years (30% to 50%) vs the absolute risk reduction (4% to 5.9%), revascularization seems less attractive.¹⁹

Relative risk reduction in death or stroke with carotid surgery is 30%–50%; absolute risk reduction is 4%–5.9%

The benefit may be further diminished if we consider only strokes related to large vessels, since up to 45% of strokes in patients with carotid disease are lacunar or cardioembolic.²⁴ Assessing for prevention of large-vessel stroke using the ACAS data, the benefit of carotid endarterectomy for prevention of stroke is further decreased to a 3.5% absolute risk reduction, and the number needed to treat for 2 years increases from 62 to 111.^24,25 Nevertheless, revascularization is necessary in appropriately selected patients, as a cerebrovascular event can cause life-altering changes to a patient’s cognitive, emotional, and physical condition.²⁶

Medical therapy—and surgery—are evolving

The optimal medical management used in the landmark studies was significantly different from what is currently recommended. The ACAS trial¹⁸ used only aspirin as optimal medical management, with no mention of statins. In the ACST trial,^2,3 the use of statins increased over time, from 7% to 11% at the beginning of the trial to 80% to 82% at the end.

On the other hand, the ACAS¹ surgeons were required to have an excellent safety record to participate. This might have compromised the trial’s validity or our ability to generalize its conclusions.

Recent data from Abbott¹⁷ suggested a loss of a statistically significant surgical advantage in prevention of ipsilateral stroke and transient ischemic attack from the early 1990s. This is most likely explained by improved medical therapy, since there was a 22% increase in baseline proportion of patients receiving antiplatelet therapy from 1985 to 2007, with 60% of patients taking antihypertensive drugs and 30% of patients taking lipid-lowering drugs. Moreover, since 2001, the annual rates of ipsilateral stroke in patients receiving medical management alone fell below those of patients who underwent carotid endarterectomy in the ACAS trial.

The analysis by Abbott¹⁷ has major limitations: inclusion of small studies, many crossover patients, and heterogeneity. In support of this allegation, a small trial (33 patients) reported a risk of stroke ipsilateral to an asymptomatic carotid stenosis as low as 0.34% per year.²⁵ Even when contrasting the outcomes of medical therapy against those of current carotid endarterectomy, in which the rate of perioperative stroke and death have fallen to 0.88% to 1.7%,^17,27,28 there is concern that the risk associated with surgery may outweigh the long-term benefit.

Flaws in the landmark trials

Beyond the debate of the questionable benefit of revascularization, well-defined flaws in the landmark trials weaken or limit their influence on current treatment guidelines and protocols for deciding whether to revascularize.

No significant benefit was found for patients over age 75.^2,3 This was thought to be due to decreased life expectancy, since the benefit from revascularization becomes significant after 3 years from intervention.^1–3 Also, studies have shown that increasing age is associated with a higher risk of perioperative stroke and death.^20,21

Women showed no benefit at 5 years and only a trend toward benefit at 10 years (P = .05),² likely from a higher rate of periprocedural strokes.

Blacks and Hispanics were underrepresented in the landmark studies,¹⁹ while one observational study reported a higher incidence of in-hospital stroke after carotid endarterectomy in black patients (6.6%) than in white patients (2%).²⁹

When associated with contralateral carotid occlusion, carotid endarterectomy carries a higher risk of perioperative stroke or death.^23,30,31

Carotid revascularization failed to reduce the risk of death—the total number of deaths within 10 years was not significantly reduced by immediate carotid endarterectomy compared with deferring the procedure.²

EVIDENCE SUPPORTING OPTIMAL MEDICAL MANAGEMENT

Optimal medical therapy mainly consists of antiplatelet therapy, blood pressure management, diabetic glycemic control, and statin therapy along with lifestyle changes including smoking cessation, exercise, and weight loss (Table 3).⁹ Detailed recommendations are provided in the American Heart Association/American Stroke Association guidelines for primary prevention of stroke.³²

Antiplatelet therapy has been shown to reduce the incidence of stroke by 25%. There is no added benefit in combining antiplatelet agents unless the patient has concomitant symptomatic coronary artery disease, recent coronary stenting, or severe peripheral artery disease.^33,34

Blood pressure control can reduce the incidence of stroke by 30% to 40%, and recent data suggest that drugs working on the renin-angiotensin system offer more benefit than beta-blockers for the same reduction in blood pressure.^34,35

Diabetic glycemic control is supported, as higher hemoglobin A_1c and fasting glucose values are associated with higher relative risk of stroke.^32,36,37 However, the stroke rate does not differ significantly between patients receiving intensive therapy and those receiving standard therapy.³⁴

Statins actually shrink carotid plaques and reduce the risk of stroke by 15% for each 10% reduction in low-density lipoprotein cholesterol. It is estimated that statin therapy confers a 30% relative risk reduction of stroke over 20 years.^34,38–41

Smoking increases the overall risk of stroke by 150%, making its cessation mandatory.⁴²

HIGH-RISK FEATURES FOR STROKE IN ASYMPTOMATIC CAROTID STENOSIS

Studies have tried to identify risk factors for stroke, so that patients at high risk could undergo revascularization and benefit from it. However, no well-defined high-risk features have yet been described that would identify patients who would benefit from early surgery.

For instance, no correlation has been found between age, sex, diabetes mellitus, lipid levels, or smoking and progression of disease.⁴³ In contrast, having either contralateral symptomatic carotid disease or contralateral total occlusion translated into a higher ipsilateral stroke risk.¹⁸ And in several studies, the 5-year risk of ipsilateral stroke was as high as 16.2% for those with 60% to 99% stenosis.^1,2,18,24,43

Features of the plaque itself

More recently, there has been a focus on plaque evaluation to predict outcomes.

Statins shrink carotid plaques and reduce the risk of stroke by 15% for each 10% reduction in LDL-C

Percent stenosis. An increased risk of death or stroke has been reported with higher degrees of stenosis or plaque progression.^44,45 The gross annual risk of ipsilateral stroke increases from 1.5% with stenosis of 60% to 70%, to 4.2% with stenosis of 71% to 90%, and to 7% with stenosis of 91% to 99%. Nevertheless, current data are insufficient to determine whether there is increasing benefit from surgery with increasing degree of stenosis in asymptomatic carotid disease.^1,3,24,44

Plaque progression translates to a 7.2% absolute increase in the incidence of stroke (1.1% if the plaque is stable vs 8.3% if the plaque is progressing). Interestingly, plaque progression to greater than 80% stenosis results in worse outcomes (relative risk 3.4, 95% CI 1.5–7.8) compared with the same level of stenosis without recent progression.³³

Intimal wall thickening of more than 1.15 mm confers a hazard ratio for stroke of 3 (95% CI 1.48–6.11).⁴⁶

Increased echolucency also confers a hazard ratio for stroke of 3 (95% CI 1.4–8.0).⁴⁶

A low gray-scale median (a surrogate of plaque composition) and plaque area have been identified as independent predictors of ipsilateral events.⁴⁴

Embolic signals on transcranial Doppler ultrasonography (Figure 1) have been associated with a hazard ratio for stroke of 2.54 over 2 years.⁴⁷

Carotid plaques predominantly composed of lipid-rich necrotic cores carry a higher risk of stroke (hazard ratio 7.2, 95% CI 1.12–46.20).⁴⁸

High tensile stress (circumferential wall tension divided by the intima-media thickness), and fibrous cap thickening (< 500 µm) predict plaque rupture.⁴⁹

Plaque ulceration. The risk of stroke increases with worsening degree of plaque ulceration: 0.4% per year for type A ulcerated plaques (small minimal excavations) compared with 12.5% for type B (large obvious excavations) and type C (multiple cavities or cavernous).⁵⁰

Low cerebrovascular reactivity. Perfusion studies such as cerebrovascular reactivity evaluate changes in cerebral blood flow in response to a stimulus such as inhaled carbon dioxide, breath-holding, or acetazolamide. This may provide a useful index of cerebral vascular function. For instance, low reactivity has been associated with ipsilateral ischemic events (odds ratio 14.4, 95% CI 2.63–78.74, P = .0021).^51,52 Silvestrini et al⁵³ reported that the incidence of ipsilateral cerebrovascular ischemic events was 4.1% per year in patients who had normal cerebral vasoreactivity during breath-holding, vs 13.9% in those with low cerebral reactivity.

BEST MEDICAL THERAPY, ALONE OR COMBINED WITH REVASCULARIZATION

For carotid revascularization to be a viable option for asymptomatic carotid stenosis, the morbidity and mortality rates associated with the operation must be less than the incidence of neurologic events in patients who do not undergo the operation.⁵⁴ An important caveat is that the longer a patient survives after carotid endarterectomy, the greater the potential benefit, since the adverse consequences of surgery are generally limited to the perioperative period.¹⁹

The current evidence regarding medical management of asymptomatic carotid stenosis suggests that the rate of ipsilateral stroke is now lower than it was in the control groups in the landmark trials.^{2,3,17,45,47,55,56} Ultimately, adherence to current best medical management takes priority over the decision to revascularize. The best current medical therapy includes, but is not limited to, antithrombotic therapy, statin therapy, blood pressure control, diabetes management, smoking cessation, and lifestyle changes (Table 3).

As noted above, stroke risk seems variable in the asymptomatic population according to the presence or absence of risk factors. Yet no well-defined “high-risk stroke profile” has been identified. Therefore, a patient-by-patient decision based on best available evidence should identify patients who may benefit from carotid revascularization. If asymptomatic carotid stenosis of 70% to 99% is found, factors that favor revascularization are male sex, younger age, and longer life expectancy (Figure 2).

For those with intermediate or high-risk surgical features, uncertainty exists in management since no studies have compared revascularization against medical management only in this group of patients.¹ However, data from high-risk cohorts had high enough complication rates in both intervention arms to question the benefit of revascularization over medical therapy.^20,21 Therefore, the individual perioperative risk of stroke, myocardial infarction, and death must be weighed against the potential benefit of revascularization for each patient.

If revascularization is pursued, studies have demonstrated that carotid artery stenting is not inferior to endarterectomy^15,16 in high-surgical-risk patients. However, the revascularization approach must be tailored to the patient profile, since stenting demonstrated a lower risk of periprocedural myocardial infarction but a higher risk of stroke compared with endarteretomy.²⁰

Finally, the current acceptable risks of perioperative stroke and death must be revised if revascularization is elected. Current data suggest that a lower threshold—around 1.4%—can be used.²⁰ Moreover, further guidelines must determine the impact of adding myocardial infarction to the tolerable perioperative risks, since it has been excluded from main trials and guidelines.²⁰

Carotid artery disease that is asymptomatic poses a dilemma: Should the patient undergo revascularization (surgical carotid endarterectomy or percutaneous stenting) or receive medical therapy alone?

On one hand, because one consequence of carotid atherosclerosis—ischemic stroke—can be devastating or deadly, many physicians and patients would rather “do something,” ie, proceed with surgery. Furthermore, several randomized trials^1–4 found carotid endarterectomy superior to medical therapy.

On the other hand, these trials were conducted in the 1990s. Surgery has improved since then, but so has medical therapy. And if we re-examine the data from the trials in terms of the absolute risk reduction and number needed to treat, as opposed to the relative risk reduction, surgery may appear less beneficial.

Needed is a way to identify patients who would benefit from surgery and those who would more likely be harmed. Research in that direction is ongoing.

Here, we present a simple algorithmic approach to managing asymptomatic carotid artery stenosis based on the patient’s age, sex, and life expectancy. Our approach is based on a review of the best available evidence.

UP TO 8% OF ADULTS HAVE STENOSIS

Stroke is the third largest cause of death in the United States and the leading cause of disability.⁵ From 10% to 15% of strokes are associated with carotid artery stenosis.^6,7

The prevalence of asymptomatic carotid disease, defined as stenosis greater than 50%, ranges from 4% to 8% in adults.⁸

However, major societies recommend against screening for carotid stenosis in the general population.^9–12 Similarly, the US Preventive Services Task Force also discourages the use of carotid auscultation as screening in the general population (Table 1).¹³ Generally, cases of asymptomatic carotid stenosis are diagnosed by ultrasonography after the patient’s physician happens to hear a bruit during a routine examination, during a preoperative assessment, or after the patient suffers a transient ischemic attack or stroke on the contralateral side.

CLASS II RECOMMENDATIONS FOR SURGERY OR STENTING

There are well-established guidelines for managing symptomatic carotid disease,¹⁴ based on evidence from the North American Symptomatic Carotid Endarterectomy Trial¹⁵ and the European Carotid Surgery Trial,¹⁶ both from 1998. But how to manage asymptomatic carotid disease remains uncertain.

If stenosis of the internal carotid artery is greater than 70% on ultrasonography, computed tomography, or magnetic resonance imaging, and if the risk of perioperative stroke and death is low (< 3%), current guidelines¹⁴ give carotid endarterectomy a class IIa recommendation (ie, evidence is conflicting, but the weight of evidence is in favor), and they give prophylactic carotid artery stenting with optimal medical treatment a class IIb recommendation (efficacy is less well established).⁵

But medical management has improved, and new data suggest that this improvement may override the minimal net benefit of intervention in some patients.¹⁷ Some authors suggest that it is best to use patient characteristics and imaging features to guide treatment.¹⁸

EVIDENCE TO SUPPORT CAROTID REVASCULARIZATION

Three major trials (Table 2) published nearly 20 years ago provide the foundation of the current guidelines:

• the Endarterectomy for Asymptomatic Carotid Atherosclerosis Study (ACAS)¹
• the Asymptomatic Carotid Surgery Trial (ACST)^2,3
• the Veterans Affairs (VA) Cooperative Study.⁴

A Cochrane review of these trials,¹⁹ where medical therapy consisted only of aspirin and little use of statin therapy, found that carotid endarterectomy reduced the rate of perioperative stroke or death or any subsequent stroke in the next 3 years by 31% (relative risk 69%, 95% confidence interval [CI] 0.57–0.83). “Perioperative” was defined as the period from randomization until 30 days after surgery in the surgical group and an equivalent period in the medical group.

Moreover, carotid endarterectomy reduced the rate of disabling or fatal nonperioperative stroke by 50% compared with medical management alone.^1,2,19 Patients who had contralateral symptomatic disease or who had undergone contralateral carotid endarterectomy seemed to benefit more from the procedure than those who had not.¹⁹

Also, the ACST investigators found that revascularization was associated with a reduction in contralateral strokes (which occurred in 39 vs 64 patients, P = .01) independent of contralateral symptoms or contralateral carotid endarterectomy.^2,3 The exact mechanism is unknown but could be related to better blood pressure control and risk factor modification after carotid endarterectomy.

Another factor supporting revascularization is that the outcomes of revascularization have improved over time. In 2010, the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)²⁰ reported a 30-day periprocedural incidence of death or stroke of only 1.4%, compared with 2.9% in the earlier landmark trials.

Stenting is a noninferior alternative

For patients who have asymptomatic stenosis greater than 80% on color duplex ultrasonography and a risk of stroke or death during carotid endarterectomy that is prohibitively high (> 3%), carotid stenting has proved to be a noninferior alternative.^21,22

The Stenting and Angioplasty With Protection of Patients With High Risk for Endarterectomy (SAPPHIRE) trial²¹ reported a risk of death, stroke, or myocardial infarction of about 5% at 30 days and 10% at 1 year after stenting. A recent observational study revealed lower perioperative complication rates, with a risk of death or stroke of about 3%, which satisfy current guideline requirements.²³

To be deemed at high surgical risk and therefore eligible for the SAPPHIRE trial,²¹ patients had to have clinically significant cardiac disease, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal-nerve palsy, recurrent stenosis after carotid endarterectomy, previous radical neck surgery or radiation therapy to the neck, or age greater than 80.

EVIDENCE AGAINST CAROTID REVASCULARIZATION

Although carotid revascularization has evidence to support it, further interpretation of the data may lessen its apparent benefits.

Small absolute benefit, high number needed to treat

If we compare the relative risk reduction for the outcome of perioperative death or any stroke over 5 years (30% to 50%) vs the absolute risk reduction (4% to 5.9%), revascularization seems less attractive.¹⁹

Relative risk reduction in death or stroke with carotid surgery is 30%–50%; absolute risk reduction is 4%–5.9%

The benefit may be further diminished if we consider only strokes related to large vessels, since up to 45% of strokes in patients with carotid disease are lacunar or cardioembolic.²⁴ Assessing for prevention of large-vessel stroke using the ACAS data, the benefit of carotid endarterectomy for prevention of stroke is further decreased to a 3.5% absolute risk reduction, and the number needed to treat for 2 years increases from 62 to 111.^24,25 Nevertheless, revascularization is necessary in appropriately selected patients, as a cerebrovascular event can cause life-altering changes to a patient’s cognitive, emotional, and physical condition.²⁶

Medical therapy—and surgery—are evolving

The optimal medical management used in the landmark studies was significantly different from what is currently recommended. The ACAS trial¹⁸ used only aspirin as optimal medical management, with no mention of statins. In the ACST trial,^2,3 the use of statins increased over time, from 7% to 11% at the beginning of the trial to 80% to 82% at the end.

On the other hand, the ACAS¹ surgeons were required to have an excellent safety record to participate. This might have compromised the trial’s validity or our ability to generalize its conclusions.

Recent data from Abbott¹⁷ suggested a loss of a statistically significant surgical advantage in prevention of ipsilateral stroke and transient ischemic attack from the early 1990s. This is most likely explained by improved medical therapy, since there was a 22% increase in baseline proportion of patients receiving antiplatelet therapy from 1985 to 2007, with 60% of patients taking antihypertensive drugs and 30% of patients taking lipid-lowering drugs. Moreover, since 2001, the annual rates of ipsilateral stroke in patients receiving medical management alone fell below those of patients who underwent carotid endarterectomy in the ACAS trial.

The analysis by Abbott¹⁷ has major limitations: inclusion of small studies, many crossover patients, and heterogeneity. In support of this allegation, a small trial (33 patients) reported a risk of stroke ipsilateral to an asymptomatic carotid stenosis as low as 0.34% per year.²⁵ Even when contrasting the outcomes of medical therapy against those of current carotid endarterectomy, in which the rate of perioperative stroke and death have fallen to 0.88% to 1.7%,^17,27,28 there is concern that the risk associated with surgery may outweigh the long-term benefit.

Flaws in the landmark trials

Beyond the debate of the questionable benefit of revascularization, well-defined flaws in the landmark trials weaken or limit their influence on current treatment guidelines and protocols for deciding whether to revascularize.

No significant benefit was found for patients over age 75.^2,3 This was thought to be due to decreased life expectancy, since the benefit from revascularization becomes significant after 3 years from intervention.^1–3 Also, studies have shown that increasing age is associated with a higher risk of perioperative stroke and death.^20,21

Women showed no benefit at 5 years and only a trend toward benefit at 10 years (P = .05),² likely from a higher rate of periprocedural strokes.

Blacks and Hispanics were underrepresented in the landmark studies,¹⁹ while one observational study reported a higher incidence of in-hospital stroke after carotid endarterectomy in black patients (6.6%) than in white patients (2%).²⁹

When associated with contralateral carotid occlusion, carotid endarterectomy carries a higher risk of perioperative stroke or death.^23,30,31

Carotid revascularization failed to reduce the risk of death—the total number of deaths within 10 years was not significantly reduced by immediate carotid endarterectomy compared with deferring the procedure.²

EVIDENCE SUPPORTING OPTIMAL MEDICAL MANAGEMENT

Optimal medical therapy mainly consists of antiplatelet therapy, blood pressure management, diabetic glycemic control, and statin therapy along with lifestyle changes including smoking cessation, exercise, and weight loss (Table 3).⁹ Detailed recommendations are provided in the American Heart Association/American Stroke Association guidelines for primary prevention of stroke.³²

Antiplatelet therapy has been shown to reduce the incidence of stroke by 25%. There is no added benefit in combining antiplatelet agents unless the patient has concomitant symptomatic coronary artery disease, recent coronary stenting, or severe peripheral artery disease.^33,34

Blood pressure control can reduce the incidence of stroke by 30% to 40%, and recent data suggest that drugs working on the renin-angiotensin system offer more benefit than beta-blockers for the same reduction in blood pressure.^34,35

Diabetic glycemic control is supported, as higher hemoglobin A_1c and fasting glucose values are associated with higher relative risk of stroke.^32,36,37 However, the stroke rate does not differ significantly between patients receiving intensive therapy and those receiving standard therapy.³⁴

Statins actually shrink carotid plaques and reduce the risk of stroke by 15% for each 10% reduction in low-density lipoprotein cholesterol. It is estimated that statin therapy confers a 30% relative risk reduction of stroke over 20 years.^34,38–41

Smoking increases the overall risk of stroke by 150%, making its cessation mandatory.⁴²

HIGH-RISK FEATURES FOR STROKE IN ASYMPTOMATIC CAROTID STENOSIS

Studies have tried to identify risk factors for stroke, so that patients at high risk could undergo revascularization and benefit from it. However, no well-defined high-risk features have yet been described that would identify patients who would benefit from early surgery.

For instance, no correlation has been found between age, sex, diabetes mellitus, lipid levels, or smoking and progression of disease.⁴³ In contrast, having either contralateral symptomatic carotid disease or contralateral total occlusion translated into a higher ipsilateral stroke risk.¹⁸ And in several studies, the 5-year risk of ipsilateral stroke was as high as 16.2% for those with 60% to 99% stenosis.^1,2,18,24,43

Features of the plaque itself

More recently, there has been a focus on plaque evaluation to predict outcomes.

Statins shrink carotid plaques and reduce the risk of stroke by 15% for each 10% reduction in LDL-C

Percent stenosis. An increased risk of death or stroke has been reported with higher degrees of stenosis or plaque progression.^44,45 The gross annual risk of ipsilateral stroke increases from 1.5% with stenosis of 60% to 70%, to 4.2% with stenosis of 71% to 90%, and to 7% with stenosis of 91% to 99%. Nevertheless, current data are insufficient to determine whether there is increasing benefit from surgery with increasing degree of stenosis in asymptomatic carotid disease.^1,3,24,44

Plaque progression translates to a 7.2% absolute increase in the incidence of stroke (1.1% if the plaque is stable vs 8.3% if the plaque is progressing). Interestingly, plaque progression to greater than 80% stenosis results in worse outcomes (relative risk 3.4, 95% CI 1.5–7.8) compared with the same level of stenosis without recent progression.³³

Intimal wall thickening of more than 1.15 mm confers a hazard ratio for stroke of 3 (95% CI 1.48–6.11).⁴⁶

Increased echolucency also confers a hazard ratio for stroke of 3 (95% CI 1.4–8.0).⁴⁶

A low gray-scale median (a surrogate of plaque composition) and plaque area have been identified as independent predictors of ipsilateral events.⁴⁴

Embolic signals on transcranial Doppler ultrasonography (Figure 1) have been associated with a hazard ratio for stroke of 2.54 over 2 years.⁴⁷

Carotid plaques predominantly composed of lipid-rich necrotic cores carry a higher risk of stroke (hazard ratio 7.2, 95% CI 1.12–46.20).⁴⁸

High tensile stress (circumferential wall tension divided by the intima-media thickness), and fibrous cap thickening (< 500 µm) predict plaque rupture.⁴⁹

Plaque ulceration. The risk of stroke increases with worsening degree of plaque ulceration: 0.4% per year for type A ulcerated plaques (small minimal excavations) compared with 12.5% for type B (large obvious excavations) and type C (multiple cavities or cavernous).⁵⁰

Low cerebrovascular reactivity. Perfusion studies such as cerebrovascular reactivity evaluate changes in cerebral blood flow in response to a stimulus such as inhaled carbon dioxide, breath-holding, or acetazolamide. This may provide a useful index of cerebral vascular function. For instance, low reactivity has been associated with ipsilateral ischemic events (odds ratio 14.4, 95% CI 2.63–78.74, P = .0021).^51,52 Silvestrini et al⁵³ reported that the incidence of ipsilateral cerebrovascular ischemic events was 4.1% per year in patients who had normal cerebral vasoreactivity during breath-holding, vs 13.9% in those with low cerebral reactivity.

BEST MEDICAL THERAPY, ALONE OR COMBINED WITH REVASCULARIZATION

For carotid revascularization to be a viable option for asymptomatic carotid stenosis, the morbidity and mortality rates associated with the operation must be less than the incidence of neurologic events in patients who do not undergo the operation.⁵⁴ An important caveat is that the longer a patient survives after carotid endarterectomy, the greater the potential benefit, since the adverse consequences of surgery are generally limited to the perioperative period.¹⁹

The current evidence regarding medical management of asymptomatic carotid stenosis suggests that the rate of ipsilateral stroke is now lower than it was in the control groups in the landmark trials.^{2,3,17,45,47,55,56} Ultimately, adherence to current best medical management takes priority over the decision to revascularize. The best current medical therapy includes, but is not limited to, antithrombotic therapy, statin therapy, blood pressure control, diabetes management, smoking cessation, and lifestyle changes (Table 3).

As noted above, stroke risk seems variable in the asymptomatic population according to the presence or absence of risk factors. Yet no well-defined “high-risk stroke profile” has been identified. Therefore, a patient-by-patient decision based on best available evidence should identify patients who may benefit from carotid revascularization. If asymptomatic carotid stenosis of 70% to 99% is found, factors that favor revascularization are male sex, younger age, and longer life expectancy (Figure 2).

For those with intermediate or high-risk surgical features, uncertainty exists in management since no studies have compared revascularization against medical management only in this group of patients.¹ However, data from high-risk cohorts had high enough complication rates in both intervention arms to question the benefit of revascularization over medical therapy.^20,21 Therefore, the individual perioperative risk of stroke, myocardial infarction, and death must be weighed against the potential benefit of revascularization for each patient.

If revascularization is pursued, studies have demonstrated that carotid artery stenting is not inferior to endarterectomy^15,16 in high-surgical-risk patients. However, the revascularization approach must be tailored to the patient profile, since stenting demonstrated a lower risk of periprocedural myocardial infarction but a higher risk of stroke compared with endarteretomy.²⁰

Finally, the current acceptable risks of perioperative stroke and death must be revised if revascularization is elected. Current data suggest that a lower threshold—around 1.4%—can be used.²⁰ Moreover, further guidelines must determine the impact of adding myocardial infarction to the tolerable perioperative risks, since it has been excluded from main trials and guidelines.²⁰

Carotid artery disease that is asymptomatic poses a dilemma: Should the patient undergo revascularization (surgical carotid endarterectomy or percutaneous stenting) or receive medical therapy alone?

On one hand, because one consequence of carotid atherosclerosis—ischemic stroke—can be devastating or deadly, many physicians and patients would rather “do something,” ie, proceed with surgery. Furthermore, several randomized trials^1–4 found carotid endarterectomy superior to medical therapy.

On the other hand, these trials were conducted in the 1990s. Surgery has improved since then, but so has medical therapy. And if we re-examine the data from the trials in terms of the absolute risk reduction and number needed to treat, as opposed to the relative risk reduction, surgery may appear less beneficial.

Needed is a way to identify patients who would benefit from surgery and those who would more likely be harmed. Research in that direction is ongoing.

Here, we present a simple algorithmic approach to managing asymptomatic carotid artery stenosis based on the patient’s age, sex, and life expectancy. Our approach is based on a review of the best available evidence.

UP TO 8% OF ADULTS HAVE STENOSIS

Stroke is the third largest cause of death in the United States and the leading cause of disability.⁵ From 10% to 15% of strokes are associated with carotid artery stenosis.^6,7

The prevalence of asymptomatic carotid disease, defined as stenosis greater than 50%, ranges from 4% to 8% in adults.⁸

However, major societies recommend against screening for carotid stenosis in the general population.^9–12 Similarly, the US Preventive Services Task Force also discourages the use of carotid auscultation as screening in the general population (Table 1).¹³ Generally, cases of asymptomatic carotid stenosis are diagnosed by ultrasonography after the patient’s physician happens to hear a bruit during a routine examination, during a preoperative assessment, or after the patient suffers a transient ischemic attack or stroke on the contralateral side.

CLASS II RECOMMENDATIONS FOR SURGERY OR STENTING

There are well-established guidelines for managing symptomatic carotid disease,¹⁴ based on evidence from the North American Symptomatic Carotid Endarterectomy Trial¹⁵ and the European Carotid Surgery Trial,¹⁶ both from 1998. But how to manage asymptomatic carotid disease remains uncertain.

If stenosis of the internal carotid artery is greater than 70% on ultrasonography, computed tomography, or magnetic resonance imaging, and if the risk of perioperative stroke and death is low (< 3%), current guidelines¹⁴ give carotid endarterectomy a class IIa recommendation (ie, evidence is conflicting, but the weight of evidence is in favor), and they give prophylactic carotid artery stenting with optimal medical treatment a class IIb recommendation (efficacy is less well established).⁵

But medical management has improved, and new data suggest that this improvement may override the minimal net benefit of intervention in some patients.¹⁷ Some authors suggest that it is best to use patient characteristics and imaging features to guide treatment.¹⁸

EVIDENCE TO SUPPORT CAROTID REVASCULARIZATION

Three major trials (Table 2) published nearly 20 years ago provide the foundation of the current guidelines:

• the Endarterectomy for Asymptomatic Carotid Atherosclerosis Study (ACAS)¹
• the Asymptomatic Carotid Surgery Trial (ACST)^2,3
• the Veterans Affairs (VA) Cooperative Study.⁴

A Cochrane review of these trials,¹⁹ where medical therapy consisted only of aspirin and little use of statin therapy, found that carotid endarterectomy reduced the rate of perioperative stroke or death or any subsequent stroke in the next 3 years by 31% (relative risk 69%, 95% confidence interval [CI] 0.57–0.83). “Perioperative” was defined as the period from randomization until 30 days after surgery in the surgical group and an equivalent period in the medical group.

Moreover, carotid endarterectomy reduced the rate of disabling or fatal nonperioperative stroke by 50% compared with medical management alone.^1,2,19 Patients who had contralateral symptomatic disease or who had undergone contralateral carotid endarterectomy seemed to benefit more from the procedure than those who had not.¹⁹

Also, the ACST investigators found that revascularization was associated with a reduction in contralateral strokes (which occurred in 39 vs 64 patients, P = .01) independent of contralateral symptoms or contralateral carotid endarterectomy.^2,3 The exact mechanism is unknown but could be related to better blood pressure control and risk factor modification after carotid endarterectomy.

Another factor supporting revascularization is that the outcomes of revascularization have improved over time. In 2010, the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)²⁰ reported a 30-day periprocedural incidence of death or stroke of only 1.4%, compared with 2.9% in the earlier landmark trials.

Stenting is a noninferior alternative

For patients who have asymptomatic stenosis greater than 80% on color duplex ultrasonography and a risk of stroke or death during carotid endarterectomy that is prohibitively high (> 3%), carotid stenting has proved to be a noninferior alternative.^21,22

The Stenting and Angioplasty With Protection of Patients With High Risk for Endarterectomy (SAPPHIRE) trial²¹ reported a risk of death, stroke, or myocardial infarction of about 5% at 30 days and 10% at 1 year after stenting. A recent observational study revealed lower perioperative complication rates, with a risk of death or stroke of about 3%, which satisfy current guideline requirements.²³

To be deemed at high surgical risk and therefore eligible for the SAPPHIRE trial,²¹ patients had to have clinically significant cardiac disease, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal-nerve palsy, recurrent stenosis after carotid endarterectomy, previous radical neck surgery or radiation therapy to the neck, or age greater than 80.

EVIDENCE AGAINST CAROTID REVASCULARIZATION

Although carotid revascularization has evidence to support it, further interpretation of the data may lessen its apparent benefits.

Small absolute benefit, high number needed to treat

If we compare the relative risk reduction for the outcome of perioperative death or any stroke over 5 years (30% to 50%) vs the absolute risk reduction (4% to 5.9%), revascularization seems less attractive.¹⁹

Relative risk reduction in death or stroke with carotid surgery is 30%–50%; absolute risk reduction is 4%–5.9%

The benefit may be further diminished if we consider only strokes related to large vessels, since up to 45% of strokes in patients with carotid disease are lacunar or cardioembolic.²⁴ Assessing for prevention of large-vessel stroke using the ACAS data, the benefit of carotid endarterectomy for prevention of stroke is further decreased to a 3.5% absolute risk reduction, and the number needed to treat for 2 years increases from 62 to 111.^24,25 Nevertheless, revascularization is necessary in appropriately selected patients, as a cerebrovascular event can cause life-altering changes to a patient’s cognitive, emotional, and physical condition.²⁶

Medical therapy—and surgery—are evolving

The optimal medical management used in the landmark studies was significantly different from what is currently recommended. The ACAS trial¹⁸ used only aspirin as optimal medical management, with no mention of statins. In the ACST trial,^2,3 the use of statins increased over time, from 7% to 11% at the beginning of the trial to 80% to 82% at the end.

On the other hand, the ACAS¹ surgeons were required to have an excellent safety record to participate. This might have compromised the trial’s validity or our ability to generalize its conclusions.

Recent data from Abbott¹⁷ suggested a loss of a statistically significant surgical advantage in prevention of ipsilateral stroke and transient ischemic attack from the early 1990s. This is most likely explained by improved medical therapy, since there was a 22% increase in baseline proportion of patients receiving antiplatelet therapy from 1985 to 2007, with 60% of patients taking antihypertensive drugs and 30% of patients taking lipid-lowering drugs. Moreover, since 2001, the annual rates of ipsilateral stroke in patients receiving medical management alone fell below those of patients who underwent carotid endarterectomy in the ACAS trial.

The analysis by Abbott¹⁷ has major limitations: inclusion of small studies, many crossover patients, and heterogeneity. In support of this allegation, a small trial (33 patients) reported a risk of stroke ipsilateral to an asymptomatic carotid stenosis as low as 0.34% per year.²⁵ Even when contrasting the outcomes of medical therapy against those of current carotid endarterectomy, in which the rate of perioperative stroke and death have fallen to 0.88% to 1.7%,^17,27,28 there is concern that the risk associated with surgery may outweigh the long-term benefit.

Flaws in the landmark trials

Beyond the debate of the questionable benefit of revascularization, well-defined flaws in the landmark trials weaken or limit their influence on current treatment guidelines and protocols for deciding whether to revascularize.

No significant benefit was found for patients over age 75.^2,3 This was thought to be due to decreased life expectancy, since the benefit from revascularization becomes significant after 3 years from intervention.^1–3 Also, studies have shown that increasing age is associated with a higher risk of perioperative stroke and death.^20,21

Women showed no benefit at 5 years and only a trend toward benefit at 10 years (P = .05),² likely from a higher rate of periprocedural strokes.

Blacks and Hispanics were underrepresented in the landmark studies,¹⁹ while one observational study reported a higher incidence of in-hospital stroke after carotid endarterectomy in black patients (6.6%) than in white patients (2%).²⁹

When associated with contralateral carotid occlusion, carotid endarterectomy carries a higher risk of perioperative stroke or death.^23,30,31

Carotid revascularization failed to reduce the risk of death—the total number of deaths within 10 years was not significantly reduced by immediate carotid endarterectomy compared with deferring the procedure.²

EVIDENCE SUPPORTING OPTIMAL MEDICAL MANAGEMENT

Optimal medical therapy mainly consists of antiplatelet therapy, blood pressure management, diabetic glycemic control, and statin therapy along with lifestyle changes including smoking cessation, exercise, and weight loss (Table 3).⁹ Detailed recommendations are provided in the American Heart Association/American Stroke Association guidelines for primary prevention of stroke.³²

Antiplatelet therapy has been shown to reduce the incidence of stroke by 25%. There is no added benefit in combining antiplatelet agents unless the patient has concomitant symptomatic coronary artery disease, recent coronary stenting, or severe peripheral artery disease.^33,34

Blood pressure control can reduce the incidence of stroke by 30% to 40%, and recent data suggest that drugs working on the renin-angiotensin system offer more benefit than beta-blockers for the same reduction in blood pressure.^34,35

Diabetic glycemic control is supported, as higher hemoglobin A_1c and fasting glucose values are associated with higher relative risk of stroke.^32,36,37 However, the stroke rate does not differ significantly between patients receiving intensive therapy and those receiving standard therapy.³⁴

Statins actually shrink carotid plaques and reduce the risk of stroke by 15% for each 10% reduction in low-density lipoprotein cholesterol. It is estimated that statin therapy confers a 30% relative risk reduction of stroke over 20 years.^34,38–41

Smoking increases the overall risk of stroke by 150%, making its cessation mandatory.⁴²

HIGH-RISK FEATURES FOR STROKE IN ASYMPTOMATIC CAROTID STENOSIS

Studies have tried to identify risk factors for stroke, so that patients at high risk could undergo revascularization and benefit from it. However, no well-defined high-risk features have yet been described that would identify patients who would benefit from early surgery.

For instance, no correlation has been found between age, sex, diabetes mellitus, lipid levels, or smoking and progression of disease.⁴³ In contrast, having either contralateral symptomatic carotid disease or contralateral total occlusion translated into a higher ipsilateral stroke risk.¹⁸ And in several studies, the 5-year risk of ipsilateral stroke was as high as 16.2% for those with 60% to 99% stenosis.^1,2,18,24,43

Features of the plaque itself

More recently, there has been a focus on plaque evaluation to predict outcomes.

Statins shrink carotid plaques and reduce the risk of stroke by 15% for each 10% reduction in LDL-C

Percent stenosis. An increased risk of death or stroke has been reported with higher degrees of stenosis or plaque progression.^44,45 The gross annual risk of ipsilateral stroke increases from 1.5% with stenosis of 60% to 70%, to 4.2% with stenosis of 71% to 90%, and to 7% with stenosis of 91% to 99%. Nevertheless, current data are insufficient to determine whether there is increasing benefit from surgery with increasing degree of stenosis in asymptomatic carotid disease.^1,3,24,44

Plaque progression translates to a 7.2% absolute increase in the incidence of stroke (1.1% if the plaque is stable vs 8.3% if the plaque is progressing). Interestingly, plaque progression to greater than 80% stenosis results in worse outcomes (relative risk 3.4, 95% CI 1.5–7.8) compared with the same level of stenosis without recent progression.³³

Intimal wall thickening of more than 1.15 mm confers a hazard ratio for stroke of 3 (95% CI 1.48–6.11).⁴⁶

Increased echolucency also confers a hazard ratio for stroke of 3 (95% CI 1.4–8.0).⁴⁶

A low gray-scale median (a surrogate of plaque composition) and plaque area have been identified as independent predictors of ipsilateral events.⁴⁴

Embolic signals on transcranial Doppler ultrasonography (Figure 1) have been associated with a hazard ratio for stroke of 2.54 over 2 years.⁴⁷

Carotid plaques predominantly composed of lipid-rich necrotic cores carry a higher risk of stroke (hazard ratio 7.2, 95% CI 1.12–46.20).⁴⁸

High tensile stress (circumferential wall tension divided by the intima-media thickness), and fibrous cap thickening (< 500 µm) predict plaque rupture.⁴⁹

Plaque ulceration. The risk of stroke increases with worsening degree of plaque ulceration: 0.4% per year for type A ulcerated plaques (small minimal excavations) compared with 12.5% for type B (large obvious excavations) and type C (multiple cavities or cavernous).⁵⁰

Low cerebrovascular reactivity. Perfusion studies such as cerebrovascular reactivity evaluate changes in cerebral blood flow in response to a stimulus such as inhaled carbon dioxide, breath-holding, or acetazolamide. This may provide a useful index of cerebral vascular function. For instance, low reactivity has been associated with ipsilateral ischemic events (odds ratio 14.4, 95% CI 2.63–78.74, P = .0021).^51,52 Silvestrini et al⁵³ reported that the incidence of ipsilateral cerebrovascular ischemic events was 4.1% per year in patients who had normal cerebral vasoreactivity during breath-holding, vs 13.9% in those with low cerebral reactivity.

BEST MEDICAL THERAPY, ALONE OR COMBINED WITH REVASCULARIZATION

For carotid revascularization to be a viable option for asymptomatic carotid stenosis, the morbidity and mortality rates associated with the operation must be less than the incidence of neurologic events in patients who do not undergo the operation.⁵⁴ An important caveat is that the longer a patient survives after carotid endarterectomy, the greater the potential benefit, since the adverse consequences of surgery are generally limited to the perioperative period.¹⁹

The current evidence regarding medical management of asymptomatic carotid stenosis suggests that the rate of ipsilateral stroke is now lower than it was in the control groups in the landmark trials.^{2,3,17,45,47,55,56} Ultimately, adherence to current best medical management takes priority over the decision to revascularize. The best current medical therapy includes, but is not limited to, antithrombotic therapy, statin therapy, blood pressure control, diabetes management, smoking cessation, and lifestyle changes (Table 3).

As noted above, stroke risk seems variable in the asymptomatic population according to the presence or absence of risk factors. Yet no well-defined “high-risk stroke profile” has been identified. Therefore, a patient-by-patient decision based on best available evidence should identify patients who may benefit from carotid revascularization. If asymptomatic carotid stenosis of 70% to 99% is found, factors that favor revascularization are male sex, younger age, and longer life expectancy (Figure 2).

For those with intermediate or high-risk surgical features, uncertainty exists in management since no studies have compared revascularization against medical management only in this group of patients.¹ However, data from high-risk cohorts had high enough complication rates in both intervention arms to question the benefit of revascularization over medical therapy.^20,21 Therefore, the individual perioperative risk of stroke, myocardial infarction, and death must be weighed against the potential benefit of revascularization for each patient.

If revascularization is pursued, studies have demonstrated that carotid artery stenting is not inferior to endarterectomy^15,16 in high-surgical-risk patients. However, the revascularization approach must be tailored to the patient profile, since stenting demonstrated a lower risk of periprocedural myocardial infarction but a higher risk of stroke compared with endarteretomy.²⁰

Finally, the current acceptable risks of perioperative stroke and death must be revised if revascularization is elected. Current data suggest that a lower threshold—around 1.4%—can be used.²⁰ Moreover, further guidelines must determine the impact of adding myocardial infarction to the tolerable perioperative risks, since it has been excluded from main trials and guidelines.²⁰

In Reply: We appreciate the comments of Dr. Saeed and colleagues. As stated in our article, given that the patients included in the FREEDOM trial represent a select group with diabetes and multivessel coronary artery disease, they may not represent all patients encountered in a real-world setting. We highlighted that only 10% of the patients screened were included for randomization, which limits the generalizability of the results. Also, the overall patient population may not be at high risk, as evidenced by low mean EuroSCORE and SYNTAX scores and by the low proportion of patients with ejection fractions less than 40%. However, patients with left main coronary artery disease (even without diabetes) have been shown to have better outcomes with coronary artery bypass grafting than with PCI, although a head-to-head trial in a diabetic subgroup is currently not available.^1,2 In addition, it is important to realize that the FREEDOM trial deals with stable angina; therefore, the results may not extend to patients with acute coronary syndrome wherein primary PCI remains the most feasible option in most cases.

Diabetes mellitus is independently associated with complex, accelerated, and multifocal coronary artery disease. Therefore, outcomes after revascularization (with bypass grafting or PCI) are worse in diabetic patients than in those without diabetes. However, this association does not prove the superiority of PCI over bypass grafting.

As we stated in our paper, the FREEDOM trial did not clearly define the strategy for arterial grafts in patients undergoing bypass grafting. The mean number of coronary lesions in the bypass grafting group was high (mean = 5.74), but the average number of grafts used was only 2.9, and data were not provided on the use of sequential grafting and multiple arterial conduits. Lastly, it is true that the FREEDOM trial had relatively fewer patients (18.5%) that underwent off-pump bypass grafting surgery; however, this approach has never been shown to be superior in large randomized trials.^3,4

In conclusion, no randomized trial should replace clinical judgment to define the targeted revascularization strategy for an individual patient. Rather, results from the FREEDOM trial should help support clinical decision-making in the context of the patient and the institution.

In Reply: We appreciate the comments of Dr. Saeed and colleagues. As stated in our article, given that the patients included in the FREEDOM trial represent a select group with diabetes and multivessel coronary artery disease, they may not represent all patients encountered in a real-world setting. We highlighted that only 10% of the patients screened were included for randomization, which limits the generalizability of the results. Also, the overall patient population may not be at high risk, as evidenced by low mean EuroSCORE and SYNTAX scores and by the low proportion of patients with ejection fractions less than 40%. However, patients with left main coronary artery disease (even without diabetes) have been shown to have better outcomes with coronary artery bypass grafting than with PCI, although a head-to-head trial in a diabetic subgroup is currently not available.^1,2 In addition, it is important to realize that the FREEDOM trial deals with stable angina; therefore, the results may not extend to patients with acute coronary syndrome wherein primary PCI remains the most feasible option in most cases.

Diabetes mellitus is independently associated with complex, accelerated, and multifocal coronary artery disease. Therefore, outcomes after revascularization (with bypass grafting or PCI) are worse in diabetic patients than in those without diabetes. However, this association does not prove the superiority of PCI over bypass grafting.

As we stated in our paper, the FREEDOM trial did not clearly define the strategy for arterial grafts in patients undergoing bypass grafting. The mean number of coronary lesions in the bypass grafting group was high (mean = 5.74), but the average number of grafts used was only 2.9, and data were not provided on the use of sequential grafting and multiple arterial conduits. Lastly, it is true that the FREEDOM trial had relatively fewer patients (18.5%) that underwent off-pump bypass grafting surgery; however, this approach has never been shown to be superior in large randomized trials.^3,4

In conclusion, no randomized trial should replace clinical judgment to define the targeted revascularization strategy for an individual patient. Rather, results from the FREEDOM trial should help support clinical decision-making in the context of the patient and the institution.

In Reply: We appreciate the comments of Dr. Saeed and colleagues. As stated in our article, given that the patients included in the FREEDOM trial represent a select group with diabetes and multivessel coronary artery disease, they may not represent all patients encountered in a real-world setting. We highlighted that only 10% of the patients screened were included for randomization, which limits the generalizability of the results. Also, the overall patient population may not be at high risk, as evidenced by low mean EuroSCORE and SYNTAX scores and by the low proportion of patients with ejection fractions less than 40%. However, patients with left main coronary artery disease (even without diabetes) have been shown to have better outcomes with coronary artery bypass grafting than with PCI, although a head-to-head trial in a diabetic subgroup is currently not available.^1,2 In addition, it is important to realize that the FREEDOM trial deals with stable angina; therefore, the results may not extend to patients with acute coronary syndrome wherein primary PCI remains the most feasible option in most cases.

Diabetes mellitus is independently associated with complex, accelerated, and multifocal coronary artery disease. Therefore, outcomes after revascularization (with bypass grafting or PCI) are worse in diabetic patients than in those without diabetes. However, this association does not prove the superiority of PCI over bypass grafting.

As we stated in our paper, the FREEDOM trial did not clearly define the strategy for arterial grafts in patients undergoing bypass grafting. The mean number of coronary lesions in the bypass grafting group was high (mean = 5.74), but the average number of grafts used was only 2.9, and data were not provided on the use of sequential grafting and multiple arterial conduits. Lastly, it is true that the FREEDOM trial had relatively fewer patients (18.5%) that underwent off-pump bypass grafting surgery; however, this approach has never been shown to be superior in large randomized trials.^3,4

In conclusion, no randomized trial should replace clinical judgment to define the targeted revascularization strategy for an individual patient. Rather, results from the FREEDOM trial should help support clinical decision-making in the context of the patient and the institution.

Many patients with diabetes mellitus develop complex, accelerated, multifocal coronary artery disease. Moreover, if they undergo revascularization with either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI), their risk of morbidity and death afterward is higher than in those without diabetes.^1,2

Over the last 2 decades, CABG and PCI have advanced significantly, as have antithrombotic therapy and drug therapies to modify cardiovascular risk factors such as hyperlipidemia, hypertension, and diabetes.

Several earlier studies showed CABG to be more beneficial than PCI in diabetic patients with multivessel coronary artery disease.^3–5 However, the topic has been controversial, and a substantial proportion of these patients continue to undergo PCI rather than CABG.

There are two main reasons for the continued use of PCI in this population. First, PCI is evolving, with new adjuvant drugs and drugeluting stents. Many cardiologists believe that earlier trials, which did not use contemporary PCI techniques, are outdated and that current, state-of-the-art PCI may be equivalent to—if not superior to—CABG.

Second, PCI is often performed on an ad hoc basis immediately after diagnostic angiography, leaving little time for discussion with the patient about alternative treatments. In this scenario, patients are inclined to undergo PCI immediately, while they are already on the table in the catheterization suite, rather than CABG at a later date.⁶

In addition, although the current joint guide-lines of the American College of Cardiology and the American Heart Association state that CABG is preferable to PCI for patients with diabetes and multivessel coronary artery disease, they give it only a level IIa recommendation.⁷

The much-anticipated Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial⁸ was designed to settle the CABG-vs-PCI debate, thereby leading to a stronger guideline recommendation for the preferred revascularization strategy in this patient population.

WHY ARE DIABETIC PATIENTS DIFFERENT?

Diabetes mellitus is a major risk factor for premature and aggressive coronary artery disease. Several mechanisms have been proposed to explain this association.

Diabetic patients have higher concentrations of several inflammatory proteins than those without diabetes, including C-reactive protein, tumor necrosis factor, and platelet-derived soluble CD40 ligand. They also have higher levels of adhesion molecules such as vascular cell adhesion molecule-1 and intercellular adhesion molecule.^9,10 In addition, when blood sugar levels are high, platelets express more glycoprotein IIb/IIIa receptors and are therefore more prone to aggregate.¹¹

These prothrombotic and proinflammatory cytokines, in conjunction with endothelial dysfunction and metabolic disorders such as hyperglycemia, hyperlipidemia, obesity, insulin resistance, and oxidative stress, lead to accelerated atherosclerosis in patients with diabetes.¹² Also, because diabetes is a systemic disease, the atherosclerotic process is diffuse, and many patients with diabetes have left main coronary artery lesions and diffuse multivessel coronary artery disease.^13,14

Although the short-term outcomes of revascularization by any means are comparable in patients with and without diabetes, diabetic patients have lower long-term survival rates and higher rates of myocardial infarction and need for repeat procedures.¹⁵ Diabetic patients who undergo PCI have a high rate of stent thrombosis and restenosis.^16,17 Similarly, those undergoing CABG have higher rates of postoperative infection and renal and neurologic complications.^18,19

BEFORE THE FREEDOM TRIAL

The question of CABG vs PCI has plagued physicians ever since PCI came to the forefront in the 1980s. Before stents were widely used, PCI with balloon angioplasty was known to be comparable to CABG for single-vessel disease, but whether it was beneficial in patients with multivessel disease or left main disease was not entirely evident. Randomized clinical trials were launched to answer the question.

Studies of balloon angioplasty vs CABG

The BARI trial (Bypass Angioplasty Revascularization Investigation),^5,20 published in 1996, compared PCI (using balloon angioplasty without a stent) and CABG in patients with multivessel coronary artery disease (Table 1^20–29).

Between 1988 and 1991, the trial randomly assigned 1,829 patients with multivessel disease to receive either PCI or CABG and compared their long-term outcomes. Although there was no difference in mortality rates between the two groups overall, the diabetic subgroup had a significantly better survival rate with CABG than with PCI, which was sustained over a follow-up period of 10 years.⁵

BARI had a significant clinical impact at the time and led to a clinical alert by the National Heart, Lung, and Blood Institute recommending CABG over PCI for patients with diabetes. However, not everyone accepted the results, because they were based on a small number of patients (n = 353) in a retrospectively determined subgroup. Further, the BARI trial was conducted before the advent of coronary stents, which were later shown to improve outcomes after PCI. Also, optimal medical therapy after revascularization was not specified in the protocol, which likely affected outcomes.

EAST (Emory Angioplasty Versus Surgery Trial)²¹ and CABRI (Coronary Angioplasty Versus Bypass Revascularization Investigation) ²² were similar randomized trials comparing angioplasty and CABG in patients with multivessel coronary artery disease. These showed better outcomes after CABG in patients with diabetes. However, lack of statistical significance because of small sample sizes limited their clinical impact.

The ARTS trial (Arterial Revascularization Therapy Study) compared PCI (with bare-metal stents) and CABG in 1,205 patients with multivessel coronary artery disease.²³ The mortality rate did not differ significantly between two treatment groups overall or in the diabetic subgroup. However, the repeat revascularization rate was higher with PCI than with CABG.

The SoS trial (Stenting or Surgery)²⁴ had similar results.

The ERACI II trial (Argentine Randomized Study: Coronary Angioplasty With Stenting Versus Coronary Bypass Surgery in Multi-Vessel Disease)²⁵ found no difference in mortality rates at 5 years with CABG vs PCI.

These trials were criticized, as none of them routinely used glycoprotein IIb/IIIa inhibitors with PCI, which by then had been shown to reduce mortality rates.³⁰ However, these trials made it clear that restenosis requiring repeat revascularization was a major disadvantage of PCI with bare-metal stents compared with CABG in patients with diabetes. Drug-eluting stents, which significantly reduced the rates of in-stent restenosis and target-lesion revascularization, were expected to overcome this major disadvantage.

Studies of PCI with drug-eluting stents vs CABG

ARTS II was the first trial to compare PCI with drug-eluting stents vs CABG. This was a nonrandomized single-arm study of 607 patients (including 159 with diabetes) who were treated with drug-eluting stents; the outcomes were compared with the CABG group from the earlier ARTS trial.³¹

At 3 years, in the diabetic subgroup, the rates of death, myocardial infarction, and stroke were not significantly different between treatments, although a trend favored PCI. However, this comparison was limited by selection bias, as ARTS II was a nonrandomized trial in which operators chose patients for drug-eluting stents in an attempt to match already known outcomes from the CABG cohort of ARTS.

SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) was the first randomized trial comparing PCI with drug-eluting stents (in this trial, paclitaxel-eluting) vs CABG in patients with three-vessel or left main coronary artery disease.^26,27 Subgroup analysis in patients with diabetes mellitus revealed a higher rate of major adverse cardiac and cerebrovascular events (death, myocardial infarction, stroke, or repeat revascularization) in the PCI group than in the CABG patients, largely driven by higher rates of repeat revascularization after PCI.^32,33 SYNTAX was not designed to assess significant differences in rates of death.

The CARDIa trial (Coronary Artery Revascularization in Diabetes) randomized patients with diabetes and multivessel coronary artery disease to PCI (about one-third with bare-metal stents and two-thirds with drug-eluting stents) or CABG. Rates of major adverse cardiac and cerebrovascular events were higher in the PCI group, again largely driven by higher rates of repeat revascularization.⁴ CARDIa was stopped early because of a lack of enrollment and could not provide sufficient evidence to endorse one strategy over the other.

VA-CARDS (Veteran Affairs Coronary Artery Revascularization in Diabetes) randomized patients with diabetes and proximal left anterior descending artery or multivessel coronary artery disease to receive PCI with drug-eluting stents or CABG.²⁸ Although the rate of death was lower with CABG than with PCI at 2 years, the trial was underpowered and was terminated at 25% of the initial intended patient enrollment. In addition, only 9% of diabetic patients screened were angiographically eligible for the study.²⁹

Registry data. Analysis of a large data set from the National Cardiovascular Disease Registry and the Society of Thoracic Surgeons revealed a survival advantage of CABG over PCI for a follow-up period of 5 years.³⁴ However, this was a nonrandomized study, so its conclusions were not definitive.

THE FREEDOM TRIAL

Given the limitations of the trials described above, the National Heart, Lung, and Blood Institute sponsored the FREEDOM trial—an appropriately powered, randomized comparison of PCI (with drug-eluting stents) and CABG (using arterial grafting) in patients with diabetes and multivessel coronary artery disease using contemporary techniques and concomitant optimal medical therapy.⁸

FREEDOM study design

The FREEDOM trial enrolled 1,900 patients with diabetes and angiographically confirmed multivessel coronary artery disease (83% with three-vessel disease) with stenosis of more than 70% in two or more major epicardial vessels involving at least two separate coronary-artery territories. The main exclusion criteria were severe left main coronary artery stenosis (≥ 50% stenosis), class III or IV congestive heart failure, and previous CABG or valve surgery. For CABG surgery, arterial revascularization was encouraged.

Dual antiplatelet therapy was recommended for at least 12 months in patients receiving a drug-eluting stent, and optimal medical management for diabetes, hypertension, and hyperlipidemia was strongly advocated.

Between April 2005 and April 2010, 32,966 patients were screened, of whom 3,309 were eligible for the trial and 1,900 consented and were randomized (953 to the PCI group and 947 to the CABG group). The patients were followed for a minimum of 2 years and had a median follow-up time of 3.8 years. Outcomes were measured with an intention-to-treat analysis.

Study results

Patients. The groups were comparable with regard to baseline demographics and cardiac risk factors.

The mean age was 63; 29% of the patients were women, and 83% had three-vessel coronary artery disease. The mean hemoglobin A_1c was 7.8%, and the mean ejection fraction was 66%. The mean SYNTAX score, which defines the anatomic complexity of lesions, was 26 (≤ 22 is mild, 23–32 is intermediate, and ≥ 33 is high). The mean EURO score, which defines surgical risk, was 2.7 (a score ≥ 5 being associated with a lower rate of survival).

The primary composite outcome (death, nonfatal myocardial infarction, or nonfatal stroke) occurred less frequently in the CABG group than in the PCI group (Table 2). CABG was also associated with significantly lower rates of death from any cause and of myocardial infarction. Importantly, survival curves comparing the two groups diverged at 2-year follow-up. In contrast to other outcomes assessed, stroke occurred more often in the CABG group. The 5-year rates in the CABG group vs the PCI group were:

• Primary outcome—18.7% vs 26.6%, P = .005
• Death from any cause—10.9% vs 16.3%, P = .049
• Myocardial infarction—6% vs 13.9%, P < .0001
• Stroke—5.2% vs 2.4%, P = .03.

The secondary outcome (death, nonfatal myocardial infarction, nonfatal stroke, or repeat revascularization at 30 days or 12 months) had occurred significantly more often in the PCI group than in the CABG group at 1 year (16.8% vs 11.8%, P = .004), with most of the difference attributable to a higher repeat revascularization rate in the PCI group (12.6% vs 4.8%, P < .001).

Subgroup analysis. CABG was superior to PCI across all prespecified subgroups, covering the complexity of the coronary artery disease. Event rates with CABG vs PCI, by tertiles of the SYNTAX score:

• SYNTAX scores ≤ 22: 17.2% vs 23.2%
• SYNTAX scores 23–32: 17.7% vs 27.2%
• SYNTAX scores ≥ 33: 22.8% vs 30.6%.

Cost-effectiveness. Although up-front costs were higher with CABG, at $34,467 for the index hospitalization vs $25,845 for PCI (P < .001), when the in-trial results were extended to a lifetime horizon, CABG had an incremental cost-effectiveness ratio of $8,132 per quality-adjusted life-year gained vs PCI.³⁵ Traditionally, therapies are considered costeffective if the incremental cost-effectiveness ratio is less than $50,000 per quality-adjusted life-year gained.

WHY MAY CABG BE SUPERIOR IN DIABETIC PATIENTS?

The major advantage of CABG over PCI is the ability to achieve complete revascularization. Diabetic patients with coronary artery disease tend to have diffuse, multifocal disease with several stenotic lesions in multiple coronary arteries. While stents only treat the focal area of most significant occlusion, CABG may bypass all proximal vulnerable plaques that could potentially develop into culprit lesions over time, truly bypassing the diseased segments (Figure 1).

In addition, heavy calcification may not allow optimal stenting in these patients.

Use of multiple stents increases the risk of restenosis, which could lead to a higher incidence of myocardial infarction and need for repeat revascularization. This was evident in the FREEDOM trial, in which the mean number of stents per patient was 4.2. Also, some lesions need to be left untreated because of the complexity involved.

The major improvement in outcomes after CABG has resulted from using arterial conduits such as the internal mammary artery rather than the saphenous vein.³⁶ The patency rates of internal mammary artery grafts exceed 80% over 10 years.³⁷ Internal mammary artery grafting was done in 94% of patients receiving CABG in the FREEDOM trial.

WHAT DOES THIS MEAN?

FREEDOM was a landmark trial that confirmed that CABG provides significant benefit compared with contemporary PCI with drug-eluting stents in patients with diabetes mellitus and multivessel coronary artery disease. It was a large multicenter trial that was adequately powered, unlike most of the earlier trials of this topic.

Unlike previous trials in which the benefit of CABG was driven by reduction in repeat revascularizations alone, FREEDOM showed lower incidence rates of all-cause mortality and myocardial infarction with CABG than with PCI. CABG was better regardless of SYNTAX score, number of diseased vessels, ejection fraction, race, or sex of the patient, indicating that it leads to superior outcomes across a wide spectrum of patients.

An argument that cardiologists often cite when recommending PCI is that it can save money due to lower length of index hospital stay and lower procedure costs of with PCI than with CABG. However, in FREEDOM, CABG also appeared to be highly cost-effective.

FREEDOM had limitations

While FREEDOM provided robust data proving the superiority of CABG, the study had several limitations.

Although there was an overall survival benefit with CABG compared with PCI, the difference in incidence of cardiovascular deaths (which accounted for 64% of all deaths) was not statistically significant.

The trial included only patients who were eligible for both PCI and CABG. Hence, the results may not be generalizable to all diabetic patients with multivessel coronary artery disease—indeed, only 10% of those screened were considered eligible for the trial. However, it is likely that several patients screened in the FREEDOM trial may not have been eligible for PCI or CABG at the time of screening, since the revascularization decision was made by a multidisciplinary team and a more appropriate decision (either CABG or PCI) was then made.

Other factors limiting the general applicability of the results were low numbers of female patients (28.6%), black patients (6.3%), patients with an ejection fraction of 40% or less (2.5%), and patients with a low SYNTAX score (35%).

There were several unexplained observations as well. The difference in events between the treatment groups was much higher in North America than in other regions. The number of coronary lesions in the CABG group was high (mean = 5.74), but the average numbers of grafts used was only 2.9, and data were not provided regarding use of sequential grafting. Similarly, an average of only 3.5 of the six stenotic lesions per patient in the PCI group were revascularized; whether this was the result of procedural limitations with PCI was not entirely clear.

In addition, while the investigators mention that an average patient received four stents, a surprising finding was that the mean total length of the stents used was only 26 mm. This appears too small, as the usual length of one drug-eluting stent is about 20 to 30 mm.

Since only high-volume centers with good outcome data were included in the trial, the results may lack validity for patients undergoing revascularization at low-volume community centers.

It remains to be seen if the benefits of CABG will be sustained over 10 years and longer, when saphenous vein grafts tend to fail and require repeat revascularization, commonly performed with PCI. Previous data suggest that the longer the follow-up, the better the results with CABG. However, long-term results (> 10 years) in studies comparing drugeluting stents and CABG are not available.

Despite limitations, FREEDOM may change clinical practice

Despite these limitations, the FREEDOM trial has the potential to change clinical practice and strengthen current recommendations for CABG in these patients.

The trial underscored the importance of a multidisciplinary heart team approach in managing patients with complex coronary artery disease, similar to that being used in patients with severe aortic stenosis since transcatheter aortic valve replacement became available.

It should also bring an end to the practice of ad hoc PCI, especially in patients with diabetes and multivessel coronary artery disease. It is now imperative that physicians discuss current evidence for therapeutic options with the patients and their families before performing diagnostic angiography rather than immediately afterward, to give the patients ample time to make an informed decision. This is important, as most patients are likely to choose PCI in the same setting over CABG unless there is extensive discussion about the risks and benefits of both strategies done in an unbiased manner before angiography.

The fear of open heart surgery, a longer hospital stay, and a higher risk of stroke with CABG may lead some patients to choose PCI instead. In addition, factors that may preclude CABG in otherwise-eligible patients include anatomic considerations (diffuse distal vessel disease, poor conduits), individual factors (frailty, poor renal function, poor pulmonary function, patient preference), and local expertise.

Nevertheless, the patient should be presented with current evidence, and discussions regarding the optimal procedure should be held with a heart team, which should include an interventional cardiologist, a cardiothoracic surgeon, and a noninvasive cardiologist to facilitate an unbiased decision.

Regardless of the strategy chosen, the importance of compliance with optimal medical therapy (statins, antiplatelet agents, diabetes treatment) should be continuously emphasized to the patient.

WHAT DOES THE FUTURE HOLD?

Despite unequivocal evidence that CABG is superior to PCI in eligible patients with diabetes mellitus in the current era, PCI technologies continue to evolve rapidly. Newer second-generation drug-eluting stents have shown lower rates of restenosis^38,39 and may shorten the duration of post-PCI dual-antiplatelet therapy, a nuisance that has negatively affected outcomes with drug-eluting stents (because of problems of cost, poor compliance, and increased bleeding risk).

At the same time, CABG has also improved, with more extensive use of complete arterial conduits and use of an off-pump bypass technique that in theory poses a lower risk of stroke, although this has not yet been shown in a randomized trial.⁴⁰

Alternative approaches are being investigated. One of them is a hybrid procedure in which minimally invasive off-pump arterial grafting is combined with drug-eluting stents, which may reduce the risk of stroke and speed postoperative recovery.

Many patients with diabetes mellitus develop complex, accelerated, multifocal coronary artery disease. Moreover, if they undergo revascularization with either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI), their risk of morbidity and death afterward is higher than in those without diabetes.^1,2

Over the last 2 decades, CABG and PCI have advanced significantly, as have antithrombotic therapy and drug therapies to modify cardiovascular risk factors such as hyperlipidemia, hypertension, and diabetes.

Several earlier studies showed CABG to be more beneficial than PCI in diabetic patients with multivessel coronary artery disease.^3–5 However, the topic has been controversial, and a substantial proportion of these patients continue to undergo PCI rather than CABG.

There are two main reasons for the continued use of PCI in this population. First, PCI is evolving, with new adjuvant drugs and drugeluting stents. Many cardiologists believe that earlier trials, which did not use contemporary PCI techniques, are outdated and that current, state-of-the-art PCI may be equivalent to—if not superior to—CABG.

Second, PCI is often performed on an ad hoc basis immediately after diagnostic angiography, leaving little time for discussion with the patient about alternative treatments. In this scenario, patients are inclined to undergo PCI immediately, while they are already on the table in the catheterization suite, rather than CABG at a later date.⁶

In addition, although the current joint guide-lines of the American College of Cardiology and the American Heart Association state that CABG is preferable to PCI for patients with diabetes and multivessel coronary artery disease, they give it only a level IIa recommendation.⁷

The much-anticipated Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial⁸ was designed to settle the CABG-vs-PCI debate, thereby leading to a stronger guideline recommendation for the preferred revascularization strategy in this patient population.

WHY ARE DIABETIC PATIENTS DIFFERENT?

Diabetes mellitus is a major risk factor for premature and aggressive coronary artery disease. Several mechanisms have been proposed to explain this association.

Diabetic patients have higher concentrations of several inflammatory proteins than those without diabetes, including C-reactive protein, tumor necrosis factor, and platelet-derived soluble CD40 ligand. They also have higher levels of adhesion molecules such as vascular cell adhesion molecule-1 and intercellular adhesion molecule.^9,10 In addition, when blood sugar levels are high, platelets express more glycoprotein IIb/IIIa receptors and are therefore more prone to aggregate.¹¹

These prothrombotic and proinflammatory cytokines, in conjunction with endothelial dysfunction and metabolic disorders such as hyperglycemia, hyperlipidemia, obesity, insulin resistance, and oxidative stress, lead to accelerated atherosclerosis in patients with diabetes.¹² Also, because diabetes is a systemic disease, the atherosclerotic process is diffuse, and many patients with diabetes have left main coronary artery lesions and diffuse multivessel coronary artery disease.^13,14

Although the short-term outcomes of revascularization by any means are comparable in patients with and without diabetes, diabetic patients have lower long-term survival rates and higher rates of myocardial infarction and need for repeat procedures.¹⁵ Diabetic patients who undergo PCI have a high rate of stent thrombosis and restenosis.^16,17 Similarly, those undergoing CABG have higher rates of postoperative infection and renal and neurologic complications.^18,19

BEFORE THE FREEDOM TRIAL

The question of CABG vs PCI has plagued physicians ever since PCI came to the forefront in the 1980s. Before stents were widely used, PCI with balloon angioplasty was known to be comparable to CABG for single-vessel disease, but whether it was beneficial in patients with multivessel disease or left main disease was not entirely evident. Randomized clinical trials were launched to answer the question.

Studies of balloon angioplasty vs CABG

The BARI trial (Bypass Angioplasty Revascularization Investigation),^5,20 published in 1996, compared PCI (using balloon angioplasty without a stent) and CABG in patients with multivessel coronary artery disease (Table 1^20–29).

Between 1988 and 1991, the trial randomly assigned 1,829 patients with multivessel disease to receive either PCI or CABG and compared their long-term outcomes. Although there was no difference in mortality rates between the two groups overall, the diabetic subgroup had a significantly better survival rate with CABG than with PCI, which was sustained over a follow-up period of 10 years.⁵

BARI had a significant clinical impact at the time and led to a clinical alert by the National Heart, Lung, and Blood Institute recommending CABG over PCI for patients with diabetes. However, not everyone accepted the results, because they were based on a small number of patients (n = 353) in a retrospectively determined subgroup. Further, the BARI trial was conducted before the advent of coronary stents, which were later shown to improve outcomes after PCI. Also, optimal medical therapy after revascularization was not specified in the protocol, which likely affected outcomes.

EAST (Emory Angioplasty Versus Surgery Trial)²¹ and CABRI (Coronary Angioplasty Versus Bypass Revascularization Investigation) ²² were similar randomized trials comparing angioplasty and CABG in patients with multivessel coronary artery disease. These showed better outcomes after CABG in patients with diabetes. However, lack of statistical significance because of small sample sizes limited their clinical impact.

The ARTS trial (Arterial Revascularization Therapy Study) compared PCI (with bare-metal stents) and CABG in 1,205 patients with multivessel coronary artery disease.²³ The mortality rate did not differ significantly between two treatment groups overall or in the diabetic subgroup. However, the repeat revascularization rate was higher with PCI than with CABG.

The SoS trial (Stenting or Surgery)²⁴ had similar results.

The ERACI II trial (Argentine Randomized Study: Coronary Angioplasty With Stenting Versus Coronary Bypass Surgery in Multi-Vessel Disease)²⁵ found no difference in mortality rates at 5 years with CABG vs PCI.

These trials were criticized, as none of them routinely used glycoprotein IIb/IIIa inhibitors with PCI, which by then had been shown to reduce mortality rates.³⁰ However, these trials made it clear that restenosis requiring repeat revascularization was a major disadvantage of PCI with bare-metal stents compared with CABG in patients with diabetes. Drug-eluting stents, which significantly reduced the rates of in-stent restenosis and target-lesion revascularization, were expected to overcome this major disadvantage.

Studies of PCI with drug-eluting stents vs CABG

ARTS II was the first trial to compare PCI with drug-eluting stents vs CABG. This was a nonrandomized single-arm study of 607 patients (including 159 with diabetes) who were treated with drug-eluting stents; the outcomes were compared with the CABG group from the earlier ARTS trial.³¹

At 3 years, in the diabetic subgroup, the rates of death, myocardial infarction, and stroke were not significantly different between treatments, although a trend favored PCI. However, this comparison was limited by selection bias, as ARTS II was a nonrandomized trial in which operators chose patients for drug-eluting stents in an attempt to match already known outcomes from the CABG cohort of ARTS.

SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) was the first randomized trial comparing PCI with drug-eluting stents (in this trial, paclitaxel-eluting) vs CABG in patients with three-vessel or left main coronary artery disease.^26,27 Subgroup analysis in patients with diabetes mellitus revealed a higher rate of major adverse cardiac and cerebrovascular events (death, myocardial infarction, stroke, or repeat revascularization) in the PCI group than in the CABG patients, largely driven by higher rates of repeat revascularization after PCI.^32,33 SYNTAX was not designed to assess significant differences in rates of death.

The CARDIa trial (Coronary Artery Revascularization in Diabetes) randomized patients with diabetes and multivessel coronary artery disease to PCI (about one-third with bare-metal stents and two-thirds with drug-eluting stents) or CABG. Rates of major adverse cardiac and cerebrovascular events were higher in the PCI group, again largely driven by higher rates of repeat revascularization.⁴ CARDIa was stopped early because of a lack of enrollment and could not provide sufficient evidence to endorse one strategy over the other.

VA-CARDS (Veteran Affairs Coronary Artery Revascularization in Diabetes) randomized patients with diabetes and proximal left anterior descending artery or multivessel coronary artery disease to receive PCI with drug-eluting stents or CABG.²⁸ Although the rate of death was lower with CABG than with PCI at 2 years, the trial was underpowered and was terminated at 25% of the initial intended patient enrollment. In addition, only 9% of diabetic patients screened were angiographically eligible for the study.²⁹

Registry data. Analysis of a large data set from the National Cardiovascular Disease Registry and the Society of Thoracic Surgeons revealed a survival advantage of CABG over PCI for a follow-up period of 5 years.³⁴ However, this was a nonrandomized study, so its conclusions were not definitive.

THE FREEDOM TRIAL

Given the limitations of the trials described above, the National Heart, Lung, and Blood Institute sponsored the FREEDOM trial—an appropriately powered, randomized comparison of PCI (with drug-eluting stents) and CABG (using arterial grafting) in patients with diabetes and multivessel coronary artery disease using contemporary techniques and concomitant optimal medical therapy.⁸

FREEDOM study design

The FREEDOM trial enrolled 1,900 patients with diabetes and angiographically confirmed multivessel coronary artery disease (83% with three-vessel disease) with stenosis of more than 70% in two or more major epicardial vessels involving at least two separate coronary-artery territories. The main exclusion criteria were severe left main coronary artery stenosis (≥ 50% stenosis), class III or IV congestive heart failure, and previous CABG or valve surgery. For CABG surgery, arterial revascularization was encouraged.

Dual antiplatelet therapy was recommended for at least 12 months in patients receiving a drug-eluting stent, and optimal medical management for diabetes, hypertension, and hyperlipidemia was strongly advocated.

Between April 2005 and April 2010, 32,966 patients were screened, of whom 3,309 were eligible for the trial and 1,900 consented and were randomized (953 to the PCI group and 947 to the CABG group). The patients were followed for a minimum of 2 years and had a median follow-up time of 3.8 years. Outcomes were measured with an intention-to-treat analysis.

Study results

Patients. The groups were comparable with regard to baseline demographics and cardiac risk factors.

The mean age was 63; 29% of the patients were women, and 83% had three-vessel coronary artery disease. The mean hemoglobin A_1c was 7.8%, and the mean ejection fraction was 66%. The mean SYNTAX score, which defines the anatomic complexity of lesions, was 26 (≤ 22 is mild, 23–32 is intermediate, and ≥ 33 is high). The mean EURO score, which defines surgical risk, was 2.7 (a score ≥ 5 being associated with a lower rate of survival).

The primary composite outcome (death, nonfatal myocardial infarction, or nonfatal stroke) occurred less frequently in the CABG group than in the PCI group (Table 2). CABG was also associated with significantly lower rates of death from any cause and of myocardial infarction. Importantly, survival curves comparing the two groups diverged at 2-year follow-up. In contrast to other outcomes assessed, stroke occurred more often in the CABG group. The 5-year rates in the CABG group vs the PCI group were:

• Primary outcome—18.7% vs 26.6%, P = .005
• Death from any cause—10.9% vs 16.3%, P = .049
• Myocardial infarction—6% vs 13.9%, P < .0001
• Stroke—5.2% vs 2.4%, P = .03.

The secondary outcome (death, nonfatal myocardial infarction, nonfatal stroke, or repeat revascularization at 30 days or 12 months) had occurred significantly more often in the PCI group than in the CABG group at 1 year (16.8% vs 11.8%, P = .004), with most of the difference attributable to a higher repeat revascularization rate in the PCI group (12.6% vs 4.8%, P < .001).

Subgroup analysis. CABG was superior to PCI across all prespecified subgroups, covering the complexity of the coronary artery disease. Event rates with CABG vs PCI, by tertiles of the SYNTAX score:

• SYNTAX scores ≤ 22: 17.2% vs 23.2%
• SYNTAX scores 23–32: 17.7% vs 27.2%
• SYNTAX scores ≥ 33: 22.8% vs 30.6%.

Cost-effectiveness. Although up-front costs were higher with CABG, at $34,467 for the index hospitalization vs $25,845 for PCI (P < .001), when the in-trial results were extended to a lifetime horizon, CABG had an incremental cost-effectiveness ratio of $8,132 per quality-adjusted life-year gained vs PCI.³⁵ Traditionally, therapies are considered costeffective if the incremental cost-effectiveness ratio is less than $50,000 per quality-adjusted life-year gained.

WHY MAY CABG BE SUPERIOR IN DIABETIC PATIENTS?

The major advantage of CABG over PCI is the ability to achieve complete revascularization. Diabetic patients with coronary artery disease tend to have diffuse, multifocal disease with several stenotic lesions in multiple coronary arteries. While stents only treat the focal area of most significant occlusion, CABG may bypass all proximal vulnerable plaques that could potentially develop into culprit lesions over time, truly bypassing the diseased segments (Figure 1).

In addition, heavy calcification may not allow optimal stenting in these patients.

Use of multiple stents increases the risk of restenosis, which could lead to a higher incidence of myocardial infarction and need for repeat revascularization. This was evident in the FREEDOM trial, in which the mean number of stents per patient was 4.2. Also, some lesions need to be left untreated because of the complexity involved.

The major improvement in outcomes after CABG has resulted from using arterial conduits such as the internal mammary artery rather than the saphenous vein.³⁶ The patency rates of internal mammary artery grafts exceed 80% over 10 years.³⁷ Internal mammary artery grafting was done in 94% of patients receiving CABG in the FREEDOM trial.

WHAT DOES THIS MEAN?

FREEDOM was a landmark trial that confirmed that CABG provides significant benefit compared with contemporary PCI with drug-eluting stents in patients with diabetes mellitus and multivessel coronary artery disease. It was a large multicenter trial that was adequately powered, unlike most of the earlier trials of this topic.

Unlike previous trials in which the benefit of CABG was driven by reduction in repeat revascularizations alone, FREEDOM showed lower incidence rates of all-cause mortality and myocardial infarction with CABG than with PCI. CABG was better regardless of SYNTAX score, number of diseased vessels, ejection fraction, race, or sex of the patient, indicating that it leads to superior outcomes across a wide spectrum of patients.

An argument that cardiologists often cite when recommending PCI is that it can save money due to lower length of index hospital stay and lower procedure costs of with PCI than with CABG. However, in FREEDOM, CABG also appeared to be highly cost-effective.

FREEDOM had limitations

While FREEDOM provided robust data proving the superiority of CABG, the study had several limitations.

Although there was an overall survival benefit with CABG compared with PCI, the difference in incidence of cardiovascular deaths (which accounted for 64% of all deaths) was not statistically significant.

The trial included only patients who were eligible for both PCI and CABG. Hence, the results may not be generalizable to all diabetic patients with multivessel coronary artery disease—indeed, only 10% of those screened were considered eligible for the trial. However, it is likely that several patients screened in the FREEDOM trial may not have been eligible for PCI or CABG at the time of screening, since the revascularization decision was made by a multidisciplinary team and a more appropriate decision (either CABG or PCI) was then made.

Other factors limiting the general applicability of the results were low numbers of female patients (28.6%), black patients (6.3%), patients with an ejection fraction of 40% or less (2.5%), and patients with a low SYNTAX score (35%).

There were several unexplained observations as well. The difference in events between the treatment groups was much higher in North America than in other regions. The number of coronary lesions in the CABG group was high (mean = 5.74), but the average numbers of grafts used was only 2.9, and data were not provided regarding use of sequential grafting. Similarly, an average of only 3.5 of the six stenotic lesions per patient in the PCI group were revascularized; whether this was the result of procedural limitations with PCI was not entirely clear.

In addition, while the investigators mention that an average patient received four stents, a surprising finding was that the mean total length of the stents used was only 26 mm. This appears too small, as the usual length of one drug-eluting stent is about 20 to 30 mm.

Since only high-volume centers with good outcome data were included in the trial, the results may lack validity for patients undergoing revascularization at low-volume community centers.

It remains to be seen if the benefits of CABG will be sustained over 10 years and longer, when saphenous vein grafts tend to fail and require repeat revascularization, commonly performed with PCI. Previous data suggest that the longer the follow-up, the better the results with CABG. However, long-term results (> 10 years) in studies comparing drugeluting stents and CABG are not available.

Despite limitations, FREEDOM may change clinical practice

Despite these limitations, the FREEDOM trial has the potential to change clinical practice and strengthen current recommendations for CABG in these patients.

The trial underscored the importance of a multidisciplinary heart team approach in managing patients with complex coronary artery disease, similar to that being used in patients with severe aortic stenosis since transcatheter aortic valve replacement became available.

It should also bring an end to the practice of ad hoc PCI, especially in patients with diabetes and multivessel coronary artery disease. It is now imperative that physicians discuss current evidence for therapeutic options with the patients and their families before performing diagnostic angiography rather than immediately afterward, to give the patients ample time to make an informed decision. This is important, as most patients are likely to choose PCI in the same setting over CABG unless there is extensive discussion about the risks and benefits of both strategies done in an unbiased manner before angiography.

The fear of open heart surgery, a longer hospital stay, and a higher risk of stroke with CABG may lead some patients to choose PCI instead. In addition, factors that may preclude CABG in otherwise-eligible patients include anatomic considerations (diffuse distal vessel disease, poor conduits), individual factors (frailty, poor renal function, poor pulmonary function, patient preference), and local expertise.

Nevertheless, the patient should be presented with current evidence, and discussions regarding the optimal procedure should be held with a heart team, which should include an interventional cardiologist, a cardiothoracic surgeon, and a noninvasive cardiologist to facilitate an unbiased decision.

Regardless of the strategy chosen, the importance of compliance with optimal medical therapy (statins, antiplatelet agents, diabetes treatment) should be continuously emphasized to the patient.

WHAT DOES THE FUTURE HOLD?

Despite unequivocal evidence that CABG is superior to PCI in eligible patients with diabetes mellitus in the current era, PCI technologies continue to evolve rapidly. Newer second-generation drug-eluting stents have shown lower rates of restenosis^38,39 and may shorten the duration of post-PCI dual-antiplatelet therapy, a nuisance that has negatively affected outcomes with drug-eluting stents (because of problems of cost, poor compliance, and increased bleeding risk).

At the same time, CABG has also improved, with more extensive use of complete arterial conduits and use of an off-pump bypass technique that in theory poses a lower risk of stroke, although this has not yet been shown in a randomized trial.⁴⁰

Alternative approaches are being investigated. One of them is a hybrid procedure in which minimally invasive off-pump arterial grafting is combined with drug-eluting stents, which may reduce the risk of stroke and speed postoperative recovery.

Many patients with diabetes mellitus develop complex, accelerated, multifocal coronary artery disease. Moreover, if they undergo revascularization with either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI), their risk of morbidity and death afterward is higher than in those without diabetes.^1,2

Over the last 2 decades, CABG and PCI have advanced significantly, as have antithrombotic therapy and drug therapies to modify cardiovascular risk factors such as hyperlipidemia, hypertension, and diabetes.

Several earlier studies showed CABG to be more beneficial than PCI in diabetic patients with multivessel coronary artery disease.^3–5 However, the topic has been controversial, and a substantial proportion of these patients continue to undergo PCI rather than CABG.

There are two main reasons for the continued use of PCI in this population. First, PCI is evolving, with new adjuvant drugs and drugeluting stents. Many cardiologists believe that earlier trials, which did not use contemporary PCI techniques, are outdated and that current, state-of-the-art PCI may be equivalent to—if not superior to—CABG.

Second, PCI is often performed on an ad hoc basis immediately after diagnostic angiography, leaving little time for discussion with the patient about alternative treatments. In this scenario, patients are inclined to undergo PCI immediately, while they are already on the table in the catheterization suite, rather than CABG at a later date.⁶

In addition, although the current joint guide-lines of the American College of Cardiology and the American Heart Association state that CABG is preferable to PCI for patients with diabetes and multivessel coronary artery disease, they give it only a level IIa recommendation.⁷

The much-anticipated Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial⁸ was designed to settle the CABG-vs-PCI debate, thereby leading to a stronger guideline recommendation for the preferred revascularization strategy in this patient population.

WHY ARE DIABETIC PATIENTS DIFFERENT?

Diabetes mellitus is a major risk factor for premature and aggressive coronary artery disease. Several mechanisms have been proposed to explain this association.

Diabetic patients have higher concentrations of several inflammatory proteins than those without diabetes, including C-reactive protein, tumor necrosis factor, and platelet-derived soluble CD40 ligand. They also have higher levels of adhesion molecules such as vascular cell adhesion molecule-1 and intercellular adhesion molecule.^9,10 In addition, when blood sugar levels are high, platelets express more glycoprotein IIb/IIIa receptors and are therefore more prone to aggregate.¹¹

These prothrombotic and proinflammatory cytokines, in conjunction with endothelial dysfunction and metabolic disorders such as hyperglycemia, hyperlipidemia, obesity, insulin resistance, and oxidative stress, lead to accelerated atherosclerosis in patients with diabetes.¹² Also, because diabetes is a systemic disease, the atherosclerotic process is diffuse, and many patients with diabetes have left main coronary artery lesions and diffuse multivessel coronary artery disease.^13,14

Although the short-term outcomes of revascularization by any means are comparable in patients with and without diabetes, diabetic patients have lower long-term survival rates and higher rates of myocardial infarction and need for repeat procedures.¹⁵ Diabetic patients who undergo PCI have a high rate of stent thrombosis and restenosis.^16,17 Similarly, those undergoing CABG have higher rates of postoperative infection and renal and neurologic complications.^18,19

BEFORE THE FREEDOM TRIAL

The question of CABG vs PCI has plagued physicians ever since PCI came to the forefront in the 1980s. Before stents were widely used, PCI with balloon angioplasty was known to be comparable to CABG for single-vessel disease, but whether it was beneficial in patients with multivessel disease or left main disease was not entirely evident. Randomized clinical trials were launched to answer the question.

Studies of balloon angioplasty vs CABG

The BARI trial (Bypass Angioplasty Revascularization Investigation),^5,20 published in 1996, compared PCI (using balloon angioplasty without a stent) and CABG in patients with multivessel coronary artery disease (Table 1^20–29).

Between 1988 and 1991, the trial randomly assigned 1,829 patients with multivessel disease to receive either PCI or CABG and compared their long-term outcomes. Although there was no difference in mortality rates between the two groups overall, the diabetic subgroup had a significantly better survival rate with CABG than with PCI, which was sustained over a follow-up period of 10 years.⁵

BARI had a significant clinical impact at the time and led to a clinical alert by the National Heart, Lung, and Blood Institute recommending CABG over PCI for patients with diabetes. However, not everyone accepted the results, because they were based on a small number of patients (n = 353) in a retrospectively determined subgroup. Further, the BARI trial was conducted before the advent of coronary stents, which were later shown to improve outcomes after PCI. Also, optimal medical therapy after revascularization was not specified in the protocol, which likely affected outcomes.

EAST (Emory Angioplasty Versus Surgery Trial)²¹ and CABRI (Coronary Angioplasty Versus Bypass Revascularization Investigation) ²² were similar randomized trials comparing angioplasty and CABG in patients with multivessel coronary artery disease. These showed better outcomes after CABG in patients with diabetes. However, lack of statistical significance because of small sample sizes limited their clinical impact.

The ARTS trial (Arterial Revascularization Therapy Study) compared PCI (with bare-metal stents) and CABG in 1,205 patients with multivessel coronary artery disease.²³ The mortality rate did not differ significantly between two treatment groups overall or in the diabetic subgroup. However, the repeat revascularization rate was higher with PCI than with CABG.

The SoS trial (Stenting or Surgery)²⁴ had similar results.

The ERACI II trial (Argentine Randomized Study: Coronary Angioplasty With Stenting Versus Coronary Bypass Surgery in Multi-Vessel Disease)²⁵ found no difference in mortality rates at 5 years with CABG vs PCI.

These trials were criticized, as none of them routinely used glycoprotein IIb/IIIa inhibitors with PCI, which by then had been shown to reduce mortality rates.³⁰ However, these trials made it clear that restenosis requiring repeat revascularization was a major disadvantage of PCI with bare-metal stents compared with CABG in patients with diabetes. Drug-eluting stents, which significantly reduced the rates of in-stent restenosis and target-lesion revascularization, were expected to overcome this major disadvantage.

Studies of PCI with drug-eluting stents vs CABG

ARTS II was the first trial to compare PCI with drug-eluting stents vs CABG. This was a nonrandomized single-arm study of 607 patients (including 159 with diabetes) who were treated with drug-eluting stents; the outcomes were compared with the CABG group from the earlier ARTS trial.³¹

At 3 years, in the diabetic subgroup, the rates of death, myocardial infarction, and stroke were not significantly different between treatments, although a trend favored PCI. However, this comparison was limited by selection bias, as ARTS II was a nonrandomized trial in which operators chose patients for drug-eluting stents in an attempt to match already known outcomes from the CABG cohort of ARTS.

SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) was the first randomized trial comparing PCI with drug-eluting stents (in this trial, paclitaxel-eluting) vs CABG in patients with three-vessel or left main coronary artery disease.^26,27 Subgroup analysis in patients with diabetes mellitus revealed a higher rate of major adverse cardiac and cerebrovascular events (death, myocardial infarction, stroke, or repeat revascularization) in the PCI group than in the CABG patients, largely driven by higher rates of repeat revascularization after PCI.^32,33 SYNTAX was not designed to assess significant differences in rates of death.

The CARDIa trial (Coronary Artery Revascularization in Diabetes) randomized patients with diabetes and multivessel coronary artery disease to PCI (about one-third with bare-metal stents and two-thirds with drug-eluting stents) or CABG. Rates of major adverse cardiac and cerebrovascular events were higher in the PCI group, again largely driven by higher rates of repeat revascularization.⁴ CARDIa was stopped early because of a lack of enrollment and could not provide sufficient evidence to endorse one strategy over the other.

VA-CARDS (Veteran Affairs Coronary Artery Revascularization in Diabetes) randomized patients with diabetes and proximal left anterior descending artery or multivessel coronary artery disease to receive PCI with drug-eluting stents or CABG.²⁸ Although the rate of death was lower with CABG than with PCI at 2 years, the trial was underpowered and was terminated at 25% of the initial intended patient enrollment. In addition, only 9% of diabetic patients screened were angiographically eligible for the study.²⁹

Registry data. Analysis of a large data set from the National Cardiovascular Disease Registry and the Society of Thoracic Surgeons revealed a survival advantage of CABG over PCI for a follow-up period of 5 years.³⁴ However, this was a nonrandomized study, so its conclusions were not definitive.

THE FREEDOM TRIAL

Given the limitations of the trials described above, the National Heart, Lung, and Blood Institute sponsored the FREEDOM trial—an appropriately powered, randomized comparison of PCI (with drug-eluting stents) and CABG (using arterial grafting) in patients with diabetes and multivessel coronary artery disease using contemporary techniques and concomitant optimal medical therapy.⁸

FREEDOM study design

The FREEDOM trial enrolled 1,900 patients with diabetes and angiographically confirmed multivessel coronary artery disease (83% with three-vessel disease) with stenosis of more than 70% in two or more major epicardial vessels involving at least two separate coronary-artery territories. The main exclusion criteria were severe left main coronary artery stenosis (≥ 50% stenosis), class III or IV congestive heart failure, and previous CABG or valve surgery. For CABG surgery, arterial revascularization was encouraged.

Dual antiplatelet therapy was recommended for at least 12 months in patients receiving a drug-eluting stent, and optimal medical management for diabetes, hypertension, and hyperlipidemia was strongly advocated.

Between April 2005 and April 2010, 32,966 patients were screened, of whom 3,309 were eligible for the trial and 1,900 consented and were randomized (953 to the PCI group and 947 to the CABG group). The patients were followed for a minimum of 2 years and had a median follow-up time of 3.8 years. Outcomes were measured with an intention-to-treat analysis.

Study results

Patients. The groups were comparable with regard to baseline demographics and cardiac risk factors.

The mean age was 63; 29% of the patients were women, and 83% had three-vessel coronary artery disease. The mean hemoglobin A_1c was 7.8%, and the mean ejection fraction was 66%. The mean SYNTAX score, which defines the anatomic complexity of lesions, was 26 (≤ 22 is mild, 23–32 is intermediate, and ≥ 33 is high). The mean EURO score, which defines surgical risk, was 2.7 (a score ≥ 5 being associated with a lower rate of survival).

The primary composite outcome (death, nonfatal myocardial infarction, or nonfatal stroke) occurred less frequently in the CABG group than in the PCI group (Table 2). CABG was also associated with significantly lower rates of death from any cause and of myocardial infarction. Importantly, survival curves comparing the two groups diverged at 2-year follow-up. In contrast to other outcomes assessed, stroke occurred more often in the CABG group. The 5-year rates in the CABG group vs the PCI group were:

• Primary outcome—18.7% vs 26.6%, P = .005
• Death from any cause—10.9% vs 16.3%, P = .049
• Myocardial infarction—6% vs 13.9%, P < .0001
• Stroke—5.2% vs 2.4%, P = .03.

The secondary outcome (death, nonfatal myocardial infarction, nonfatal stroke, or repeat revascularization at 30 days or 12 months) had occurred significantly more often in the PCI group than in the CABG group at 1 year (16.8% vs 11.8%, P = .004), with most of the difference attributable to a higher repeat revascularization rate in the PCI group (12.6% vs 4.8%, P < .001).

Subgroup analysis. CABG was superior to PCI across all prespecified subgroups, covering the complexity of the coronary artery disease. Event rates with CABG vs PCI, by tertiles of the SYNTAX score:

• SYNTAX scores ≤ 22: 17.2% vs 23.2%
• SYNTAX scores 23–32: 17.7% vs 27.2%
• SYNTAX scores ≥ 33: 22.8% vs 30.6%.

Cost-effectiveness. Although up-front costs were higher with CABG, at $34,467 for the index hospitalization vs $25,845 for PCI (P < .001), when the in-trial results were extended to a lifetime horizon, CABG had an incremental cost-effectiveness ratio of $8,132 per quality-adjusted life-year gained vs PCI.³⁵ Traditionally, therapies are considered costeffective if the incremental cost-effectiveness ratio is less than $50,000 per quality-adjusted life-year gained.

WHY MAY CABG BE SUPERIOR IN DIABETIC PATIENTS?

The major advantage of CABG over PCI is the ability to achieve complete revascularization. Diabetic patients with coronary artery disease tend to have diffuse, multifocal disease with several stenotic lesions in multiple coronary arteries. While stents only treat the focal area of most significant occlusion, CABG may bypass all proximal vulnerable plaques that could potentially develop into culprit lesions over time, truly bypassing the diseased segments (Figure 1).

In addition, heavy calcification may not allow optimal stenting in these patients.

Use of multiple stents increases the risk of restenosis, which could lead to a higher incidence of myocardial infarction and need for repeat revascularization. This was evident in the FREEDOM trial, in which the mean number of stents per patient was 4.2. Also, some lesions need to be left untreated because of the complexity involved.

The major improvement in outcomes after CABG has resulted from using arterial conduits such as the internal mammary artery rather than the saphenous vein.³⁶ The patency rates of internal mammary artery grafts exceed 80% over 10 years.³⁷ Internal mammary artery grafting was done in 94% of patients receiving CABG in the FREEDOM trial.

WHAT DOES THIS MEAN?

FREEDOM was a landmark trial that confirmed that CABG provides significant benefit compared with contemporary PCI with drug-eluting stents in patients with diabetes mellitus and multivessel coronary artery disease. It was a large multicenter trial that was adequately powered, unlike most of the earlier trials of this topic.

Unlike previous trials in which the benefit of CABG was driven by reduction in repeat revascularizations alone, FREEDOM showed lower incidence rates of all-cause mortality and myocardial infarction with CABG than with PCI. CABG was better regardless of SYNTAX score, number of diseased vessels, ejection fraction, race, or sex of the patient, indicating that it leads to superior outcomes across a wide spectrum of patients.

An argument that cardiologists often cite when recommending PCI is that it can save money due to lower length of index hospital stay and lower procedure costs of with PCI than with CABG. However, in FREEDOM, CABG also appeared to be highly cost-effective.

FREEDOM had limitations

While FREEDOM provided robust data proving the superiority of CABG, the study had several limitations.

Although there was an overall survival benefit with CABG compared with PCI, the difference in incidence of cardiovascular deaths (which accounted for 64% of all deaths) was not statistically significant.

The trial included only patients who were eligible for both PCI and CABG. Hence, the results may not be generalizable to all diabetic patients with multivessel coronary artery disease—indeed, only 10% of those screened were considered eligible for the trial. However, it is likely that several patients screened in the FREEDOM trial may not have been eligible for PCI or CABG at the time of screening, since the revascularization decision was made by a multidisciplinary team and a more appropriate decision (either CABG or PCI) was then made.

Other factors limiting the general applicability of the results were low numbers of female patients (28.6%), black patients (6.3%), patients with an ejection fraction of 40% or less (2.5%), and patients with a low SYNTAX score (35%).

There were several unexplained observations as well. The difference in events between the treatment groups was much higher in North America than in other regions. The number of coronary lesions in the CABG group was high (mean = 5.74), but the average numbers of grafts used was only 2.9, and data were not provided regarding use of sequential grafting. Similarly, an average of only 3.5 of the six stenotic lesions per patient in the PCI group were revascularized; whether this was the result of procedural limitations with PCI was not entirely clear.

In addition, while the investigators mention that an average patient received four stents, a surprising finding was that the mean total length of the stents used was only 26 mm. This appears too small, as the usual length of one drug-eluting stent is about 20 to 30 mm.

Since only high-volume centers with good outcome data were included in the trial, the results may lack validity for patients undergoing revascularization at low-volume community centers.

It remains to be seen if the benefits of CABG will be sustained over 10 years and longer, when saphenous vein grafts tend to fail and require repeat revascularization, commonly performed with PCI. Previous data suggest that the longer the follow-up, the better the results with CABG. However, long-term results (> 10 years) in studies comparing drugeluting stents and CABG are not available.

Despite limitations, FREEDOM may change clinical practice

Despite these limitations, the FREEDOM trial has the potential to change clinical practice and strengthen current recommendations for CABG in these patients.

The trial underscored the importance of a multidisciplinary heart team approach in managing patients with complex coronary artery disease, similar to that being used in patients with severe aortic stenosis since transcatheter aortic valve replacement became available.

It should also bring an end to the practice of ad hoc PCI, especially in patients with diabetes and multivessel coronary artery disease. It is now imperative that physicians discuss current evidence for therapeutic options with the patients and their families before performing diagnostic angiography rather than immediately afterward, to give the patients ample time to make an informed decision. This is important, as most patients are likely to choose PCI in the same setting over CABG unless there is extensive discussion about the risks and benefits of both strategies done in an unbiased manner before angiography.

The fear of open heart surgery, a longer hospital stay, and a higher risk of stroke with CABG may lead some patients to choose PCI instead. In addition, factors that may preclude CABG in otherwise-eligible patients include anatomic considerations (diffuse distal vessel disease, poor conduits), individual factors (frailty, poor renal function, poor pulmonary function, patient preference), and local expertise.

Nevertheless, the patient should be presented with current evidence, and discussions regarding the optimal procedure should be held with a heart team, which should include an interventional cardiologist, a cardiothoracic surgeon, and a noninvasive cardiologist to facilitate an unbiased decision.

Regardless of the strategy chosen, the importance of compliance with optimal medical therapy (statins, antiplatelet agents, diabetes treatment) should be continuously emphasized to the patient.

WHAT DOES THE FUTURE HOLD?

Despite unequivocal evidence that CABG is superior to PCI in eligible patients with diabetes mellitus in the current era, PCI technologies continue to evolve rapidly. Newer second-generation drug-eluting stents have shown lower rates of restenosis^38,39 and may shorten the duration of post-PCI dual-antiplatelet therapy, a nuisance that has negatively affected outcomes with drug-eluting stents (because of problems of cost, poor compliance, and increased bleeding risk).

At the same time, CABG has also improved, with more extensive use of complete arterial conduits and use of an off-pump bypass technique that in theory poses a lower risk of stroke, although this has not yet been shown in a randomized trial.⁴⁰

Alternative approaches are being investigated. One of them is a hybrid procedure in which minimally invasive off-pump arterial grafting is combined with drug-eluting stents, which may reduce the risk of stroke and speed postoperative recovery.

Can a percutaneous catheter-based procedure effectively treat resistant hypertension?

Radiofrequency ablation of the renal sympathetic nerves is undergoing randomized controlled trials in patients who have resistant hypertension and other disorders that involve the sympathetic nervous system. Remarkably, the limited results available so far look good.

See related editorial

This article discusses the physiologic rationale for renal denervation, the evidence from studies in humans of the benefits, risks, and complications of the procedure, upcoming trials, and areas for future research.

DESPITE MANY TREATMENT OPTIONS, RESISTANT HYPERTENSION IS COMMON

Hypertension is a leading reason for visits to physicians in the United States and is associated with increased rates of cardiovascular disease and death.^1,2 A variety of antihypertensive agents are available, and the percentage of people with hypertension whose blood pressure is under control has increased over the past 2 decades. Nevertheless, population-based studies show that the control rate remains suboptimal.³ Effective pharmacologic treatment may be limited by inadequate doses or inappropriate combinations of antihypertensive drugs, concurrent use of agents that raise the blood pressure, noncompliance with dietary restrictions, and side effects that result in poor compliance with drug therapy.

Resistant hypertension is defined as failure to achieve goal blood pressure in patients who are adhering to full tolerated doses of an appropriate three-drug regimen that includes a diuretic.^1,4,5 If we use these criteria, many patients labelled as having resistant hypertension probably do not truly have it; instead, they are nonadherent to therapy or are on an inadequate or inappropriate regimen. Although the true prevalence of resistant hypertension is not clear, estimates from large clinical trials suggest that about 20% to 30% of hypertensive patients may meet the criteria for it.⁴ For the subset of patients who have truly resistant hypertension, nonpharmacologic treatments such as renal sympathetic denervation are an intriguing avenue.

SURGICAL SYMPATHETIC DENERVATION: TRIED AND ABANDONED IN THE 1950s

More than a half century ago, a surgical procedure, thoracolumbar sympathectomy (in which sympathetic nerve trunks and splanchnic nerves were removed), was sometimes performed to control blood pressure in patients with malignant hypertension. This was effective but caused debilitating side effects such as postural hypotension, erectile dysfunction, and syncope.

Smithwick and Thompson⁶ reported that, in 1,266 hypertensive patients who underwent this procedure and 467 medically treated controls, the 5-year mortality rates were 19% and 54%, respectively. Forty-five percent of those who survived the surgery had significantly lower blood pressure afterward, and the antihypertensive effect lasted 10 years or more.

The procedure fell out of favor due to the morbidity associated with this nonselective approach and to the increased availability of drug therapy.

THE SYMPATHETIC NERVOUS SYSTEM IS A DRIVER OF HYPERTENSION

A variety of evidence suggests that hyperactivation of the sympathetic nervous system plays a major role in initiating and maintaining hypertension. For example, drugs that inhibit the sympathetic drive at various levels have a blood-pressure-lowering effect. Further, direct intraneural recordings show a high level of sympathetic nerve activity in the muscles of hypertensive patients, who also have high levels of cardiac and renal norepinephrine “spillover”—ie, the amount of this neurotransmitter that escapes neuronal uptake and local metabolism and spills over into the circulation.⁷

The kidneys are supplied with postganglionic sympathetic nerve fibers that end in the efferent and afferent renal arterioles, the juxtaglomerular apparatus, and the renal tubular system. Studies in animals and humans have shown that an increase in efferent signals (ie, from the brain to the kidney) leads to renal vasoconstriction and decreased renal blood flow, increased renin release, and sodium retention.^8,9 Afferent signals (from the kidney to the central nervous system), which are increased in states of renal ischemia, renal parenchymal injury, and hypoxia, disinhibit the vasomotor center (the nuclei tractus solitarii) in the central nervous system, leading to increased efferent signals to the kidneys, heart, and peripheral blood vessels (Figure 1).¹⁰

Enhanced sympathetic activity in patients with hypertension may play a role in subsequent target-organ damage such as left ventricular hypertrophy, congestive heart failure, and progressive renal damage.¹¹

Studies of renal denervation in animals, using surgical and chemical techniques, have further helped to establish the role of renal sympathetic nerves in hypertension.^12,13

CATHETER-BASED RENAL DENERVATION

Renal sympathetic nerves run through the adventitia of the renal arteries in a mesh-like pattern.

In the renal denervation procedure, a specially designed catheter is inserted into a femoral artery and advanced into one of the renal arteries. There, radiofrequency energy is applied to the endoluminal surface according to a proprietary algorithm, thereby delivering thermal injury selectively to the renal sympathetic nerves without affecting the abdominal, pelvic, or lower-extremity nerves. The energy delivered is lower than that used for cardiac electrophysiologic procedures.

The nerves are not imaged or mapped before treatment. The procedure is performed on both sides, with four to six sites ablated in a longitudinal and rotational manner in 2-minute treatments at each site, to cover the full circumference (Figure 1).

In the United States, the device (Symplicity Renal Denervation System; Medtronic, Inc, Mountain View, CA) is available only for investigational use.

Below, we briefly review the studies of renal denervation to date. SYMPLICITY HTN-1 Symplicity HTN-1 was a proof-of-principle study in 45 patients with resistant hypertension (Table  1).^14,15

Effect on blood pressure. Six months after renal denervation, blood pressure was significantly lower than at baseline (−22/−11 mm Hg, 95% confidence interval [CI] 10/5 mm Hg) in 26 patients available for follow-up. At 12 months, the difference from baseline was −27/−10 mm Hg (95% CI 16/11 mm Hg) in 9 patients available for follow-up (Table 2).¹⁴

Evidence of the durability of blood pressure reduction came from an expanded cohort of 153 patients followed for 2 years after denervation.¹⁶

Further follow-up data showed a sustained and significant blood pressure reduction through 3 years after denervation (unpublished results presented at the 2012 annual meeting of the American College of Cardiology). Notably, patients who were initially considered to be nonresponders (defined as failure of their blood pressure to go down by at least 10 mm Hg) were all reported to have a clinical response at 36 months.

Adverse events. In the initial and expanded cohorts combined, one patient suffered a renal artery dissection due to manipulation of the guiding catheter before the radiofrequency energy was delivered, and three patients developed a femoral pseudoaneurysm. No other long-term arterial complications were observed.

Comments. Limitations of this study included a small number of patients, no control group, and a primary outcome of a reduction in office blood pressure rather than in ambulatory blood pressure.

Additionally, although the authors concluded that there was no significant deterioration in renal function during the study period, we should note that in an additional follow-up period in this cohort, 10 patients with available 2-year data had a decrease in estimated glomerular filtration rate (eGFR) of −16.0 mL/min/1.73 m². In 5 patients who did not have spironolactone (Aldactone) or another diuretic added after the first year of followup, a lesser but significant decrease (−7.8 mL/min/1.73 m²) was noted. The investigators surmised that denervation may enhance diuretic sensitivity, leading to prerenal azotemia in some patients.¹⁷

SYMPLICITY HTN-2

The Symplicity HTN-2 trial was a larger, randomized, efficacy study that built on the earlier results, providing additional evidence of therapeutic benefit.¹⁵

An international cohort of 106 patients with resistant hypertension, defined as systolic blood pressure of 160 mm Hg or higher (or ≥ 150 mm Hg in patients with type 2 diabetes) despite the use of three or more antihypertensive medications, were randomly assigned to undergo renal denervation with the Symplicity device (n = 52) or to continue their previous treatment with antihypertensive medications alone (n = 54). The primary effectiveness end point was the change in seated office blood pressure from baseline to 6 months (Table 1).

Effect on blood pressure. In the denervation group, at 6 months, office blood pressure had changed by a mean of −32/−12 mm Hg (standard deviation [SD] 23/11 mm Hg) compared with a mean change of 1/0 mm Hg (SD 21/10 mm Hg) in the control group. Fortyone (84%) of the 49 patients who underwent denervation had a decrease in systolic blood pressure of 10 mm Hg or more at 6 months compared with baseline values, while five (10%) had no decline in systolic blood pressure. Nineteen patients had a reduction in systolic pressure to less than 140 mm Hg in the denervation group.

A subset of patients (20 in the denervation group and 25 in the control group) underwent 24-hour ambulatory blood pressure monitoring at 6 months. This showed a similar though less pronounced fall in blood pressure in the denervation group and no change in the controls. A subanalysis that censored all data for patients whose medication was increased during the follow-up period showed a blood pressure reduction of −31/−12 mm Hg (SD 22/11 mm Hg) in the renal denervation group.

Adverse events. Procedure-related adverse events included a single femoral artery pseudoaneurysm, one case of postprocedural hypotension requiring a reduction in antihypertensive medications, and 7 (13%) of 52 patients who experienced intraprocedural bradycardia requiring atropine.

Effect on renal function. No significant difference was noted between groups in the mean change in renal function at 6 months, whether assessed by eGFR, serum creatinine level, or cystatin C level. At 6 months, no patient had a decrease of more than 50% in eGFR, although two patients who underwent renal denervation and three controls had more than a 25% decrease in eGFR.

At 6 months, the urine albumin-to-creatinine ratio had changed by a median of −3 mg/g (range −1,089 to 76) in 38 patients in the treatment group and by 1 mg/g (range −538 to 227) in 37 controls.

Most patients (88%) undergoing renal denervation underwent renal arterial imaging at 6 months, on which a single patient showed possible progression of an underlying atherosclerotic lesion that was unrelated to the procedure and that did not require intervention.

Denervation and the normal stress response. Whether renal denervation negatively affects the body’s physiologic response to stress that is normally mediated by sympathetic nerve activity was addressed in an extended investigation of Symplicity HTN-2 using cardiopulmonary exercise tests at baseline and 3 months after renal denervation.¹⁸ In the denervation group, blood pressure during exercise was significantly lower at 3 months than at baseline, but the heart rate increase at different levels of exercise was not affected. Additionally, the resting heart rate was lower and heart rate recovery after exercise improved after the procedure, particularly in patients without diabetes.

Comments. The Symplicity HTN-2 trial benefited from a randomized trial design and strict inclusion criteria of treatment resistance, but it still had notable limitations. A pretrial evaluation for causes of secondary hypertension or white-coat hypertension was not explicitly described. The control group did not undergo a sham procedure, and data analyzers were not masked to treatment assignment. Although not analyzed as a primary end point, the use of home-based and 24-hour ambulatory blood pressure assessment—measures important for determining white-coat hypertension—revealed substantial differences in blood pressure changes relative to office measurements. Because nearly all the patients (97%) were white, the generalizability of treatment results to black patients with resistant hypertension may be limited. Isolated diastolic hypertension (defined as diastolic pressure ≥ 90 mm Hg with systolic pressure < 140 mm Hg), which is more common in younger patients, was not studied.

DOES RENAL DENERVATION REDUCE SYMPATHETIC TONE?

A subgroup of 10 patients in the Symplicity HTN-1 trial whose mean 6-month office blood pressure was reduced by 22/12 mm Hg underwent assessment of renal norepinephrine spillover. A substantial (47%) reduction in renal norepinephrine spillover was noted 1 month after the procedure.¹⁴

The investigators additionally described a marked reduction in renal norepinephrine spillover from both kidneys in one patient, with a reduction of 48% from the left kidney and 75% from the right kidney 1 month after the procedure. Whole-body norepinephrine spillover in this patient was reduced by 42%. This effect was accompanied by a 50% decrease in plasma renin activity and by an increase in renal plasma flow. Aldosterone levels were not reported.¹⁹

Thus, the decrease in renal norepinephrine spillover suggests a reduction of renal efferent activity, and the decrease in total body norepinephrine spillover suggests a reduction in central sympathetic drive via the renal afferent pathway.

Microneurography in this same patient showed a gradual reduction in muscle sympathetic nerve activity to normal levels, from 56 bursts per minute at baseline to 41 at 30 days and 19 at 12 months).¹⁹ Decreased renin secretion, via circulating angiotensin II, may affect central sympathetic outflow as well.

Comments. While these findings address some of the underlying mechanisms, the small number of patients in whom these studies were done limits the generalizability of the results. The impact of the procedure on renal hemodynamics will need to be studied, including possible direct effects of the procedure, and whether there are differences in different study populations or differences based on blood pressure levels.

WHICH PATIENTS RESPOND BEST TO THIS PROCEDURE?

Although the Symplicity HTN-2 investigators report some predictors of increased reduction in blood pressure on multivariate analysis, including increased blood pressure at baseline and reduced heart rate at baseline, these are not specific enough to enable patient selection.

Interestingly, results from the expanded cohort of the Symplicity HTN-1 study found that patients on central sympatholytic agents such as clonidine had a greater reduction in blood pressure, although the reason for this is unclear.¹⁶ Identifying specific predictors of treatment success at baseline will be essential in future studies.

The earlier Symplicity trials and the ongoing Symplicity HTN-3 trial are in patients who have high blood pressure not responding to three or more antihypertensive drugs. The mean baseline systolic blood pressure in the Symplicity HTN-1 and HTN-2 trials was 178 mm Hg, and patients were taking an average of five antihypertensive drugs (Table 1). It is not known whether denervation will produce similar blood-pressure-lowering results across the spectrum of hypertension severity.

WHAT ARE THE LONG-TERM RESULTS OF DENERVATION?

Enthusiasm for the results from the Symplicity trials is tempered by concerns about the durability of the effects of the procedure, the need for better understanding of the impact of renal denervation on a wide array of pathophysiologic cascades leading to hypertension, and the effect on renal hemodynamics.

Antihypertensive efficacy has been reported to persist up to 2 years after the procedure,¹⁶ with recent unpublished data suggesting efficacy up to 3 years, but longer follow-up is needed to address whether these effects are finite.

Although reinnervation of afferent renal nerves has not been described, transplant models have shown anatomic regrowth of efferent nerves; the impact of this efferent reinnervation on blood pressure remains unclear. Experience from renal transplantation also shows that implanted kidneys that are “denervated” can still maintain fluid and electrolyte regulation.

Follow-up renal imaging in the Symplicity trials did not indicate renal artery stenosis at the sites of denervation in patients who underwent the procedure. Animal studies using the Symplicity catheter system showed renal nerve injury as evidenced by nerve fibrosis and thickened epineurium and perineurium, but no significant smooth muscle hyperplasia, arterial stenosis, or thrombosis by angiography or histology at 6 months.²⁰

WHAT ARE THE RISKS?

Adverse effects that were noted in the short term are detailed under discussion of the trials and in Table 2.

Long-term adverse events in the Symplicity HTN-2 trial that required hospitalization were reported in five patients in the denervation group and three patients in the control group (Table 2). These included transient ischemic attacks, hypertensive crises, hypotensive episodes, angina, and nausea.

Renal function was maintained for the duration of both trials, and details regarding eGFR change have been described above under the discussion of the trials.

Diffuse visceral pain at the time of the procedure is reported as an expected occurrence, managed with intravenous analgesic medications.

DOES SYMPATHETIC DENERVATION HAVE A ROLE IN OTHER CONDITIONS?

Interestingly, other sympathetically driven diseases, such as diabetes mellitus and polycystic ovary syndrome, may prove to be targets for this therapy in the future.²¹

Mahfoud et al²² conducted a pilot study in 37 patients with resistant hypertension undergoing renal denervation and 13 control patients. Fasting glucose levels declined from 118 ± 3.4 mg/dL to 108 ± 3.8 mg/dL after 3 months in the intervention group (P = .039), compared with no change in the control group. Insulin and C-peptide levels were also lower in the intervention group. The reported improvement in glucose metabolism and insulin sensitivity suggests that the beneficial effects of this procedure may extend beyond blood pressure reduction.

Brandt et al²³ reported regression of left ventricular hypertrophy and significantly improved cardiac functional parameters, including increase in ejection fraction and improved diastolic dysfunction, in a study of 46 patients who underwent renal denervation. This findings suggests a potential beneficial effect on cardiac remodeling.

Witkowski et al²⁴ reported lowering of blood pressure in 10 patients with refractory hypertension and obstructive sleep apnea who underwent renal denervation, which was accompanied by improvement of sleep apnea severity.

Ukena et al²⁵ reported reduction in ventricular tachyarrhythmias in two patients with congestive heart failure who had therapy-resistant electrical storm.

A recent pilot study in 15 patients with stage 3 and 4 chronic kidney disease (mean eGFR 31 mL/min/1.73 m²) showed significantly improved office blood pressure control up to 1 year, restoration of nocturnal dipping on 24-hour monitoring, as well as a nonsignificant trend towards increased hemoglobin levels and decreased proteinuria. No additional deterioration of renal function was reported in these patients (2 patients had renal function assessed up to 1 year).²⁶

Thus, the benefits of this procedure may extend to other diseases that have a common underlying thread of elevated sympathetic activity, by targeting the “sympathorenal” axis.²⁷

GUARDED OPTIMISM AND FUTURE DIRECTIONS

Given the well-known cardiovascular risks and health care costs associated with uncontrolled hypertension and the continued challenge that physicians face in managing it, novel therapies such as renal denervation may provide an adjunct to existing pharmacologic approaches.

While there is certainly cause for guarded optimism, especially with the striking blood pressure-lowering results seen in trials so far, it should be kept in mind that the mechanisms leading to the hypertensive response are complex and multifactorial, and further understanding of this therapy with long-term follow-up is needed. A comparison study with spironolactone, which is increasingly being used to treat resistant hypertension (in the absence of a diagnosis of primary aldosteronism)^28,29 would help to further establish the role of this procedure.

Studies of carotid baroreceptor stimulation via an implantable device have shown sustained reduction in blood pressure in patients with resistant hypertension. A study comparing this technique with renal denervation for efficacy and safety end points could be considered in the future.^30,31

The planned Symplicity HTN-3 study in the United States will be the largest trial to date, with a targeted randomization of more than 500 patients using strict enrollment criteria, including the use of maximally tolerated doses of diuretics and more focus on the use of ambulatory blood pressure monitoring and on the blinding of participants. This study will help further analysis of this technology in a more diverse population.^32,33

Future studies should be designed to clarify pathophysiologic mechanisms, patient selection criteria, effects on target organ damage, and efficacy in patients with chronic kidney disease, obesity, congestive heart failure, and in less severe forms of hypertension.

A CALL FOR PARTICIPANTS IN A CLINICAL TRIAL

The Departments of Cardiology and Nephrology and Hypertension at Cleveland Clinic are currently enrolling patients in the Symplicity HTN-3 trial. For more information, please contact George Thomas, MD ([email protected]), or Mehdi Shishehbor, DO, MPH ([email protected]), or visit www.symplifybptrial.com.

Can a percutaneous catheter-based procedure effectively treat resistant hypertension?

Radiofrequency ablation of the renal sympathetic nerves is undergoing randomized controlled trials in patients who have resistant hypertension and other disorders that involve the sympathetic nervous system. Remarkably, the limited results available so far look good.

See related editorial

This article discusses the physiologic rationale for renal denervation, the evidence from studies in humans of the benefits, risks, and complications of the procedure, upcoming trials, and areas for future research.

DESPITE MANY TREATMENT OPTIONS, RESISTANT HYPERTENSION IS COMMON

Hypertension is a leading reason for visits to physicians in the United States and is associated with increased rates of cardiovascular disease and death.^1,2 A variety of antihypertensive agents are available, and the percentage of people with hypertension whose blood pressure is under control has increased over the past 2 decades. Nevertheless, population-based studies show that the control rate remains suboptimal.³ Effective pharmacologic treatment may be limited by inadequate doses or inappropriate combinations of antihypertensive drugs, concurrent use of agents that raise the blood pressure, noncompliance with dietary restrictions, and side effects that result in poor compliance with drug therapy.

Resistant hypertension is defined as failure to achieve goal blood pressure in patients who are adhering to full tolerated doses of an appropriate three-drug regimen that includes a diuretic.^1,4,5 If we use these criteria, many patients labelled as having resistant hypertension probably do not truly have it; instead, they are nonadherent to therapy or are on an inadequate or inappropriate regimen. Although the true prevalence of resistant hypertension is not clear, estimates from large clinical trials suggest that about 20% to 30% of hypertensive patients may meet the criteria for it.⁴ For the subset of patients who have truly resistant hypertension, nonpharmacologic treatments such as renal sympathetic denervation are an intriguing avenue.

SURGICAL SYMPATHETIC DENERVATION: TRIED AND ABANDONED IN THE 1950s

More than a half century ago, a surgical procedure, thoracolumbar sympathectomy (in which sympathetic nerve trunks and splanchnic nerves were removed), was sometimes performed to control blood pressure in patients with malignant hypertension. This was effective but caused debilitating side effects such as postural hypotension, erectile dysfunction, and syncope.

Smithwick and Thompson⁶ reported that, in 1,266 hypertensive patients who underwent this procedure and 467 medically treated controls, the 5-year mortality rates were 19% and 54%, respectively. Forty-five percent of those who survived the surgery had significantly lower blood pressure afterward, and the antihypertensive effect lasted 10 years or more.

The procedure fell out of favor due to the morbidity associated with this nonselective approach and to the increased availability of drug therapy.

THE SYMPATHETIC NERVOUS SYSTEM IS A DRIVER OF HYPERTENSION

A variety of evidence suggests that hyperactivation of the sympathetic nervous system plays a major role in initiating and maintaining hypertension. For example, drugs that inhibit the sympathetic drive at various levels have a blood-pressure-lowering effect. Further, direct intraneural recordings show a high level of sympathetic nerve activity in the muscles of hypertensive patients, who also have high levels of cardiac and renal norepinephrine “spillover”—ie, the amount of this neurotransmitter that escapes neuronal uptake and local metabolism and spills over into the circulation.⁷

The kidneys are supplied with postganglionic sympathetic nerve fibers that end in the efferent and afferent renal arterioles, the juxtaglomerular apparatus, and the renal tubular system. Studies in animals and humans have shown that an increase in efferent signals (ie, from the brain to the kidney) leads to renal vasoconstriction and decreased renal blood flow, increased renin release, and sodium retention.^8,9 Afferent signals (from the kidney to the central nervous system), which are increased in states of renal ischemia, renal parenchymal injury, and hypoxia, disinhibit the vasomotor center (the nuclei tractus solitarii) in the central nervous system, leading to increased efferent signals to the kidneys, heart, and peripheral blood vessels (Figure 1).¹⁰

Enhanced sympathetic activity in patients with hypertension may play a role in subsequent target-organ damage such as left ventricular hypertrophy, congestive heart failure, and progressive renal damage.¹¹

Studies of renal denervation in animals, using surgical and chemical techniques, have further helped to establish the role of renal sympathetic nerves in hypertension.^12,13

CATHETER-BASED RENAL DENERVATION

Renal sympathetic nerves run through the adventitia of the renal arteries in a mesh-like pattern.

In the renal denervation procedure, a specially designed catheter is inserted into a femoral artery and advanced into one of the renal arteries. There, radiofrequency energy is applied to the endoluminal surface according to a proprietary algorithm, thereby delivering thermal injury selectively to the renal sympathetic nerves without affecting the abdominal, pelvic, or lower-extremity nerves. The energy delivered is lower than that used for cardiac electrophysiologic procedures.

The nerves are not imaged or mapped before treatment. The procedure is performed on both sides, with four to six sites ablated in a longitudinal and rotational manner in 2-minute treatments at each site, to cover the full circumference (Figure 1).

In the United States, the device (Symplicity Renal Denervation System; Medtronic, Inc, Mountain View, CA) is available only for investigational use.

Below, we briefly review the studies of renal denervation to date. SYMPLICITY HTN-1 Symplicity HTN-1 was a proof-of-principle study in 45 patients with resistant hypertension (Table  1).^14,15

Effect on blood pressure. Six months after renal denervation, blood pressure was significantly lower than at baseline (−22/−11 mm Hg, 95% confidence interval [CI] 10/5 mm Hg) in 26 patients available for follow-up. At 12 months, the difference from baseline was −27/−10 mm Hg (95% CI 16/11 mm Hg) in 9 patients available for follow-up (Table 2).¹⁴

Evidence of the durability of blood pressure reduction came from an expanded cohort of 153 patients followed for 2 years after denervation.¹⁶

Further follow-up data showed a sustained and significant blood pressure reduction through 3 years after denervation (unpublished results presented at the 2012 annual meeting of the American College of Cardiology). Notably, patients who were initially considered to be nonresponders (defined as failure of their blood pressure to go down by at least 10 mm Hg) were all reported to have a clinical response at 36 months.

Adverse events. In the initial and expanded cohorts combined, one patient suffered a renal artery dissection due to manipulation of the guiding catheter before the radiofrequency energy was delivered, and three patients developed a femoral pseudoaneurysm. No other long-term arterial complications were observed.

Comments. Limitations of this study included a small number of patients, no control group, and a primary outcome of a reduction in office blood pressure rather than in ambulatory blood pressure.

Additionally, although the authors concluded that there was no significant deterioration in renal function during the study period, we should note that in an additional follow-up period in this cohort, 10 patients with available 2-year data had a decrease in estimated glomerular filtration rate (eGFR) of −16.0 mL/min/1.73 m². In 5 patients who did not have spironolactone (Aldactone) or another diuretic added after the first year of followup, a lesser but significant decrease (−7.8 mL/min/1.73 m²) was noted. The investigators surmised that denervation may enhance diuretic sensitivity, leading to prerenal azotemia in some patients.¹⁷

SYMPLICITY HTN-2

The Symplicity HTN-2 trial was a larger, randomized, efficacy study that built on the earlier results, providing additional evidence of therapeutic benefit.¹⁵

An international cohort of 106 patients with resistant hypertension, defined as systolic blood pressure of 160 mm Hg or higher (or ≥ 150 mm Hg in patients with type 2 diabetes) despite the use of three or more antihypertensive medications, were randomly assigned to undergo renal denervation with the Symplicity device (n = 52) or to continue their previous treatment with antihypertensive medications alone (n = 54). The primary effectiveness end point was the change in seated office blood pressure from baseline to 6 months (Table 1).

Effect on blood pressure. In the denervation group, at 6 months, office blood pressure had changed by a mean of −32/−12 mm Hg (standard deviation [SD] 23/11 mm Hg) compared with a mean change of 1/0 mm Hg (SD 21/10 mm Hg) in the control group. Fortyone (84%) of the 49 patients who underwent denervation had a decrease in systolic blood pressure of 10 mm Hg or more at 6 months compared with baseline values, while five (10%) had no decline in systolic blood pressure. Nineteen patients had a reduction in systolic pressure to less than 140 mm Hg in the denervation group.

A subset of patients (20 in the denervation group and 25 in the control group) underwent 24-hour ambulatory blood pressure monitoring at 6 months. This showed a similar though less pronounced fall in blood pressure in the denervation group and no change in the controls. A subanalysis that censored all data for patients whose medication was increased during the follow-up period showed a blood pressure reduction of −31/−12 mm Hg (SD 22/11 mm Hg) in the renal denervation group.

Adverse events. Procedure-related adverse events included a single femoral artery pseudoaneurysm, one case of postprocedural hypotension requiring a reduction in antihypertensive medications, and 7 (13%) of 52 patients who experienced intraprocedural bradycardia requiring atropine.

Effect on renal function. No significant difference was noted between groups in the mean change in renal function at 6 months, whether assessed by eGFR, serum creatinine level, or cystatin C level. At 6 months, no patient had a decrease of more than 50% in eGFR, although two patients who underwent renal denervation and three controls had more than a 25% decrease in eGFR.

At 6 months, the urine albumin-to-creatinine ratio had changed by a median of −3 mg/g (range −1,089 to 76) in 38 patients in the treatment group and by 1 mg/g (range −538 to 227) in 37 controls.

Most patients (88%) undergoing renal denervation underwent renal arterial imaging at 6 months, on which a single patient showed possible progression of an underlying atherosclerotic lesion that was unrelated to the procedure and that did not require intervention.

Denervation and the normal stress response. Whether renal denervation negatively affects the body’s physiologic response to stress that is normally mediated by sympathetic nerve activity was addressed in an extended investigation of Symplicity HTN-2 using cardiopulmonary exercise tests at baseline and 3 months after renal denervation.¹⁸ In the denervation group, blood pressure during exercise was significantly lower at 3 months than at baseline, but the heart rate increase at different levels of exercise was not affected. Additionally, the resting heart rate was lower and heart rate recovery after exercise improved after the procedure, particularly in patients without diabetes.

Comments. The Symplicity HTN-2 trial benefited from a randomized trial design and strict inclusion criteria of treatment resistance, but it still had notable limitations. A pretrial evaluation for causes of secondary hypertension or white-coat hypertension was not explicitly described. The control group did not undergo a sham procedure, and data analyzers were not masked to treatment assignment. Although not analyzed as a primary end point, the use of home-based and 24-hour ambulatory blood pressure assessment—measures important for determining white-coat hypertension—revealed substantial differences in blood pressure changes relative to office measurements. Because nearly all the patients (97%) were white, the generalizability of treatment results to black patients with resistant hypertension may be limited. Isolated diastolic hypertension (defined as diastolic pressure ≥ 90 mm Hg with systolic pressure < 140 mm Hg), which is more common in younger patients, was not studied.

DOES RENAL DENERVATION REDUCE SYMPATHETIC TONE?

A subgroup of 10 patients in the Symplicity HTN-1 trial whose mean 6-month office blood pressure was reduced by 22/12 mm Hg underwent assessment of renal norepinephrine spillover. A substantial (47%) reduction in renal norepinephrine spillover was noted 1 month after the procedure.¹⁴

The investigators additionally described a marked reduction in renal norepinephrine spillover from both kidneys in one patient, with a reduction of 48% from the left kidney and 75% from the right kidney 1 month after the procedure. Whole-body norepinephrine spillover in this patient was reduced by 42%. This effect was accompanied by a 50% decrease in plasma renin activity and by an increase in renal plasma flow. Aldosterone levels were not reported.¹⁹

Thus, the decrease in renal norepinephrine spillover suggests a reduction of renal efferent activity, and the decrease in total body norepinephrine spillover suggests a reduction in central sympathetic drive via the renal afferent pathway.

Microneurography in this same patient showed a gradual reduction in muscle sympathetic nerve activity to normal levels, from 56 bursts per minute at baseline to 41 at 30 days and 19 at 12 months).¹⁹ Decreased renin secretion, via circulating angiotensin II, may affect central sympathetic outflow as well.

Comments. While these findings address some of the underlying mechanisms, the small number of patients in whom these studies were done limits the generalizability of the results. The impact of the procedure on renal hemodynamics will need to be studied, including possible direct effects of the procedure, and whether there are differences in different study populations or differences based on blood pressure levels.

WHICH PATIENTS RESPOND BEST TO THIS PROCEDURE?

Although the Symplicity HTN-2 investigators report some predictors of increased reduction in blood pressure on multivariate analysis, including increased blood pressure at baseline and reduced heart rate at baseline, these are not specific enough to enable patient selection.

Interestingly, results from the expanded cohort of the Symplicity HTN-1 study found that patients on central sympatholytic agents such as clonidine had a greater reduction in blood pressure, although the reason for this is unclear.¹⁶ Identifying specific predictors of treatment success at baseline will be essential in future studies.

The earlier Symplicity trials and the ongoing Symplicity HTN-3 trial are in patients who have high blood pressure not responding to three or more antihypertensive drugs. The mean baseline systolic blood pressure in the Symplicity HTN-1 and HTN-2 trials was 178 mm Hg, and patients were taking an average of five antihypertensive drugs (Table 1). It is not known whether denervation will produce similar blood-pressure-lowering results across the spectrum of hypertension severity.

WHAT ARE THE LONG-TERM RESULTS OF DENERVATION?

Enthusiasm for the results from the Symplicity trials is tempered by concerns about the durability of the effects of the procedure, the need for better understanding of the impact of renal denervation on a wide array of pathophysiologic cascades leading to hypertension, and the effect on renal hemodynamics.

Antihypertensive efficacy has been reported to persist up to 2 years after the procedure,¹⁶ with recent unpublished data suggesting efficacy up to 3 years, but longer follow-up is needed to address whether these effects are finite.

Although reinnervation of afferent renal nerves has not been described, transplant models have shown anatomic regrowth of efferent nerves; the impact of this efferent reinnervation on blood pressure remains unclear. Experience from renal transplantation also shows that implanted kidneys that are “denervated” can still maintain fluid and electrolyte regulation.

Follow-up renal imaging in the Symplicity trials did not indicate renal artery stenosis at the sites of denervation in patients who underwent the procedure. Animal studies using the Symplicity catheter system showed renal nerve injury as evidenced by nerve fibrosis and thickened epineurium and perineurium, but no significant smooth muscle hyperplasia, arterial stenosis, or thrombosis by angiography or histology at 6 months.²⁰

WHAT ARE THE RISKS?

Adverse effects that were noted in the short term are detailed under discussion of the trials and in Table 2.

Long-term adverse events in the Symplicity HTN-2 trial that required hospitalization were reported in five patients in the denervation group and three patients in the control group (Table 2). These included transient ischemic attacks, hypertensive crises, hypotensive episodes, angina, and nausea.

Renal function was maintained for the duration of both trials, and details regarding eGFR change have been described above under the discussion of the trials.

Diffuse visceral pain at the time of the procedure is reported as an expected occurrence, managed with intravenous analgesic medications.

DOES SYMPATHETIC DENERVATION HAVE A ROLE IN OTHER CONDITIONS?

Interestingly, other sympathetically driven diseases, such as diabetes mellitus and polycystic ovary syndrome, may prove to be targets for this therapy in the future.²¹

Mahfoud et al²² conducted a pilot study in 37 patients with resistant hypertension undergoing renal denervation and 13 control patients. Fasting glucose levels declined from 118 ± 3.4 mg/dL to 108 ± 3.8 mg/dL after 3 months in the intervention group (P = .039), compared with no change in the control group. Insulin and C-peptide levels were also lower in the intervention group. The reported improvement in glucose metabolism and insulin sensitivity suggests that the beneficial effects of this procedure may extend beyond blood pressure reduction.

Brandt et al²³ reported regression of left ventricular hypertrophy and significantly improved cardiac functional parameters, including increase in ejection fraction and improved diastolic dysfunction, in a study of 46 patients who underwent renal denervation. This findings suggests a potential beneficial effect on cardiac remodeling.

Witkowski et al²⁴ reported lowering of blood pressure in 10 patients with refractory hypertension and obstructive sleep apnea who underwent renal denervation, which was accompanied by improvement of sleep apnea severity.

Ukena et al²⁵ reported reduction in ventricular tachyarrhythmias in two patients with congestive heart failure who had therapy-resistant electrical storm.

A recent pilot study in 15 patients with stage 3 and 4 chronic kidney disease (mean eGFR 31 mL/min/1.73 m²) showed significantly improved office blood pressure control up to 1 year, restoration of nocturnal dipping on 24-hour monitoring, as well as a nonsignificant trend towards increased hemoglobin levels and decreased proteinuria. No additional deterioration of renal function was reported in these patients (2 patients had renal function assessed up to 1 year).²⁶

Thus, the benefits of this procedure may extend to other diseases that have a common underlying thread of elevated sympathetic activity, by targeting the “sympathorenal” axis.²⁷

GUARDED OPTIMISM AND FUTURE DIRECTIONS

Given the well-known cardiovascular risks and health care costs associated with uncontrolled hypertension and the continued challenge that physicians face in managing it, novel therapies such as renal denervation may provide an adjunct to existing pharmacologic approaches.

While there is certainly cause for guarded optimism, especially with the striking blood pressure-lowering results seen in trials so far, it should be kept in mind that the mechanisms leading to the hypertensive response are complex and multifactorial, and further understanding of this therapy with long-term follow-up is needed. A comparison study with spironolactone, which is increasingly being used to treat resistant hypertension (in the absence of a diagnosis of primary aldosteronism)^28,29 would help to further establish the role of this procedure.

Studies of carotid baroreceptor stimulation via an implantable device have shown sustained reduction in blood pressure in patients with resistant hypertension. A study comparing this technique with renal denervation for efficacy and safety end points could be considered in the future.^30,31

The planned Symplicity HTN-3 study in the United States will be the largest trial to date, with a targeted randomization of more than 500 patients using strict enrollment criteria, including the use of maximally tolerated doses of diuretics and more focus on the use of ambulatory blood pressure monitoring and on the blinding of participants. This study will help further analysis of this technology in a more diverse population.^32,33

Future studies should be designed to clarify pathophysiologic mechanisms, patient selection criteria, effects on target organ damage, and efficacy in patients with chronic kidney disease, obesity, congestive heart failure, and in less severe forms of hypertension.

A CALL FOR PARTICIPANTS IN A CLINICAL TRIAL

The Departments of Cardiology and Nephrology and Hypertension at Cleveland Clinic are currently enrolling patients in the Symplicity HTN-3 trial. For more information, please contact George Thomas, MD ([email protected]), or Mehdi Shishehbor, DO, MPH ([email protected]), or visit www.symplifybptrial.com.

Can a percutaneous catheter-based procedure effectively treat resistant hypertension?

Radiofrequency ablation of the renal sympathetic nerves is undergoing randomized controlled trials in patients who have resistant hypertension and other disorders that involve the sympathetic nervous system. Remarkably, the limited results available so far look good.

See related editorial

This article discusses the physiologic rationale for renal denervation, the evidence from studies in humans of the benefits, risks, and complications of the procedure, upcoming trials, and areas for future research.

DESPITE MANY TREATMENT OPTIONS, RESISTANT HYPERTENSION IS COMMON

Hypertension is a leading reason for visits to physicians in the United States and is associated with increased rates of cardiovascular disease and death.^1,2 A variety of antihypertensive agents are available, and the percentage of people with hypertension whose blood pressure is under control has increased over the past 2 decades. Nevertheless, population-based studies show that the control rate remains suboptimal.³ Effective pharmacologic treatment may be limited by inadequate doses or inappropriate combinations of antihypertensive drugs, concurrent use of agents that raise the blood pressure, noncompliance with dietary restrictions, and side effects that result in poor compliance with drug therapy.

Resistant hypertension is defined as failure to achieve goal blood pressure in patients who are adhering to full tolerated doses of an appropriate three-drug regimen that includes a diuretic.^1,4,5 If we use these criteria, many patients labelled as having resistant hypertension probably do not truly have it; instead, they are nonadherent to therapy or are on an inadequate or inappropriate regimen. Although the true prevalence of resistant hypertension is not clear, estimates from large clinical trials suggest that about 20% to 30% of hypertensive patients may meet the criteria for it.⁴ For the subset of patients who have truly resistant hypertension, nonpharmacologic treatments such as renal sympathetic denervation are an intriguing avenue.

SURGICAL SYMPATHETIC DENERVATION: TRIED AND ABANDONED IN THE 1950s

More than a half century ago, a surgical procedure, thoracolumbar sympathectomy (in which sympathetic nerve trunks and splanchnic nerves were removed), was sometimes performed to control blood pressure in patients with malignant hypertension. This was effective but caused debilitating side effects such as postural hypotension, erectile dysfunction, and syncope.

Smithwick and Thompson⁶ reported that, in 1,266 hypertensive patients who underwent this procedure and 467 medically treated controls, the 5-year mortality rates were 19% and 54%, respectively. Forty-five percent of those who survived the surgery had significantly lower blood pressure afterward, and the antihypertensive effect lasted 10 years or more.

The procedure fell out of favor due to the morbidity associated with this nonselective approach and to the increased availability of drug therapy.

THE SYMPATHETIC NERVOUS SYSTEM IS A DRIVER OF HYPERTENSION

A variety of evidence suggests that hyperactivation of the sympathetic nervous system plays a major role in initiating and maintaining hypertension. For example, drugs that inhibit the sympathetic drive at various levels have a blood-pressure-lowering effect. Further, direct intraneural recordings show a high level of sympathetic nerve activity in the muscles of hypertensive patients, who also have high levels of cardiac and renal norepinephrine “spillover”—ie, the amount of this neurotransmitter that escapes neuronal uptake and local metabolism and spills over into the circulation.⁷

The kidneys are supplied with postganglionic sympathetic nerve fibers that end in the efferent and afferent renal arterioles, the juxtaglomerular apparatus, and the renal tubular system. Studies in animals and humans have shown that an increase in efferent signals (ie, from the brain to the kidney) leads to renal vasoconstriction and decreased renal blood flow, increased renin release, and sodium retention.^8,9 Afferent signals (from the kidney to the central nervous system), which are increased in states of renal ischemia, renal parenchymal injury, and hypoxia, disinhibit the vasomotor center (the nuclei tractus solitarii) in the central nervous system, leading to increased efferent signals to the kidneys, heart, and peripheral blood vessels (Figure 1).¹⁰

Enhanced sympathetic activity in patients with hypertension may play a role in subsequent target-organ damage such as left ventricular hypertrophy, congestive heart failure, and progressive renal damage.¹¹

Studies of renal denervation in animals, using surgical and chemical techniques, have further helped to establish the role of renal sympathetic nerves in hypertension.^12,13

CATHETER-BASED RENAL DENERVATION

Renal sympathetic nerves run through the adventitia of the renal arteries in a mesh-like pattern.

In the renal denervation procedure, a specially designed catheter is inserted into a femoral artery and advanced into one of the renal arteries. There, radiofrequency energy is applied to the endoluminal surface according to a proprietary algorithm, thereby delivering thermal injury selectively to the renal sympathetic nerves without affecting the abdominal, pelvic, or lower-extremity nerves. The energy delivered is lower than that used for cardiac electrophysiologic procedures.

The nerves are not imaged or mapped before treatment. The procedure is performed on both sides, with four to six sites ablated in a longitudinal and rotational manner in 2-minute treatments at each site, to cover the full circumference (Figure 1).

In the United States, the device (Symplicity Renal Denervation System; Medtronic, Inc, Mountain View, CA) is available only for investigational use.

Below, we briefly review the studies of renal denervation to date. SYMPLICITY HTN-1 Symplicity HTN-1 was a proof-of-principle study in 45 patients with resistant hypertension (Table  1).^14,15

Effect on blood pressure. Six months after renal denervation, blood pressure was significantly lower than at baseline (−22/−11 mm Hg, 95% confidence interval [CI] 10/5 mm Hg) in 26 patients available for follow-up. At 12 months, the difference from baseline was −27/−10 mm Hg (95% CI 16/11 mm Hg) in 9 patients available for follow-up (Table 2).¹⁴

Evidence of the durability of blood pressure reduction came from an expanded cohort of 153 patients followed for 2 years after denervation.¹⁶

Further follow-up data showed a sustained and significant blood pressure reduction through 3 years after denervation (unpublished results presented at the 2012 annual meeting of the American College of Cardiology). Notably, patients who were initially considered to be nonresponders (defined as failure of their blood pressure to go down by at least 10 mm Hg) were all reported to have a clinical response at 36 months.

Adverse events. In the initial and expanded cohorts combined, one patient suffered a renal artery dissection due to manipulation of the guiding catheter before the radiofrequency energy was delivered, and three patients developed a femoral pseudoaneurysm. No other long-term arterial complications were observed.

Comments. Limitations of this study included a small number of patients, no control group, and a primary outcome of a reduction in office blood pressure rather than in ambulatory blood pressure.

Additionally, although the authors concluded that there was no significant deterioration in renal function during the study period, we should note that in an additional follow-up period in this cohort, 10 patients with available 2-year data had a decrease in estimated glomerular filtration rate (eGFR) of −16.0 mL/min/1.73 m². In 5 patients who did not have spironolactone (Aldactone) or another diuretic added after the first year of followup, a lesser but significant decrease (−7.8 mL/min/1.73 m²) was noted. The investigators surmised that denervation may enhance diuretic sensitivity, leading to prerenal azotemia in some patients.¹⁷

SYMPLICITY HTN-2

The Symplicity HTN-2 trial was a larger, randomized, efficacy study that built on the earlier results, providing additional evidence of therapeutic benefit.¹⁵

An international cohort of 106 patients with resistant hypertension, defined as systolic blood pressure of 160 mm Hg or higher (or ≥ 150 mm Hg in patients with type 2 diabetes) despite the use of three or more antihypertensive medications, were randomly assigned to undergo renal denervation with the Symplicity device (n = 52) or to continue their previous treatment with antihypertensive medications alone (n = 54). The primary effectiveness end point was the change in seated office blood pressure from baseline to 6 months (Table 1).

Effect on blood pressure. In the denervation group, at 6 months, office blood pressure had changed by a mean of −32/−12 mm Hg (standard deviation [SD] 23/11 mm Hg) compared with a mean change of 1/0 mm Hg (SD 21/10 mm Hg) in the control group. Fortyone (84%) of the 49 patients who underwent denervation had a decrease in systolic blood pressure of 10 mm Hg or more at 6 months compared with baseline values, while five (10%) had no decline in systolic blood pressure. Nineteen patients had a reduction in systolic pressure to less than 140 mm Hg in the denervation group.

A subset of patients (20 in the denervation group and 25 in the control group) underwent 24-hour ambulatory blood pressure monitoring at 6 months. This showed a similar though less pronounced fall in blood pressure in the denervation group and no change in the controls. A subanalysis that censored all data for patients whose medication was increased during the follow-up period showed a blood pressure reduction of −31/−12 mm Hg (SD 22/11 mm Hg) in the renal denervation group.

Adverse events. Procedure-related adverse events included a single femoral artery pseudoaneurysm, one case of postprocedural hypotension requiring a reduction in antihypertensive medications, and 7 (13%) of 52 patients who experienced intraprocedural bradycardia requiring atropine.

Effect on renal function. No significant difference was noted between groups in the mean change in renal function at 6 months, whether assessed by eGFR, serum creatinine level, or cystatin C level. At 6 months, no patient had a decrease of more than 50% in eGFR, although two patients who underwent renal denervation and three controls had more than a 25% decrease in eGFR.

At 6 months, the urine albumin-to-creatinine ratio had changed by a median of −3 mg/g (range −1,089 to 76) in 38 patients in the treatment group and by 1 mg/g (range −538 to 227) in 37 controls.

Most patients (88%) undergoing renal denervation underwent renal arterial imaging at 6 months, on which a single patient showed possible progression of an underlying atherosclerotic lesion that was unrelated to the procedure and that did not require intervention.

Denervation and the normal stress response. Whether renal denervation negatively affects the body’s physiologic response to stress that is normally mediated by sympathetic nerve activity was addressed in an extended investigation of Symplicity HTN-2 using cardiopulmonary exercise tests at baseline and 3 months after renal denervation.¹⁸ In the denervation group, blood pressure during exercise was significantly lower at 3 months than at baseline, but the heart rate increase at different levels of exercise was not affected. Additionally, the resting heart rate was lower and heart rate recovery after exercise improved after the procedure, particularly in patients without diabetes.

Comments. The Symplicity HTN-2 trial benefited from a randomized trial design and strict inclusion criteria of treatment resistance, but it still had notable limitations. A pretrial evaluation for causes of secondary hypertension or white-coat hypertension was not explicitly described. The control group did not undergo a sham procedure, and data analyzers were not masked to treatment assignment. Although not analyzed as a primary end point, the use of home-based and 24-hour ambulatory blood pressure assessment—measures important for determining white-coat hypertension—revealed substantial differences in blood pressure changes relative to office measurements. Because nearly all the patients (97%) were white, the generalizability of treatment results to black patients with resistant hypertension may be limited. Isolated diastolic hypertension (defined as diastolic pressure ≥ 90 mm Hg with systolic pressure < 140 mm Hg), which is more common in younger patients, was not studied.

DOES RENAL DENERVATION REDUCE SYMPATHETIC TONE?

A subgroup of 10 patients in the Symplicity HTN-1 trial whose mean 6-month office blood pressure was reduced by 22/12 mm Hg underwent assessment of renal norepinephrine spillover. A substantial (47%) reduction in renal norepinephrine spillover was noted 1 month after the procedure.¹⁴

The investigators additionally described a marked reduction in renal norepinephrine spillover from both kidneys in one patient, with a reduction of 48% from the left kidney and 75% from the right kidney 1 month after the procedure. Whole-body norepinephrine spillover in this patient was reduced by 42%. This effect was accompanied by a 50% decrease in plasma renin activity and by an increase in renal plasma flow. Aldosterone levels were not reported.¹⁹

Thus, the decrease in renal norepinephrine spillover suggests a reduction of renal efferent activity, and the decrease in total body norepinephrine spillover suggests a reduction in central sympathetic drive via the renal afferent pathway.

Microneurography in this same patient showed a gradual reduction in muscle sympathetic nerve activity to normal levels, from 56 bursts per minute at baseline to 41 at 30 days and 19 at 12 months).¹⁹ Decreased renin secretion, via circulating angiotensin II, may affect central sympathetic outflow as well.

Comments. While these findings address some of the underlying mechanisms, the small number of patients in whom these studies were done limits the generalizability of the results. The impact of the procedure on renal hemodynamics will need to be studied, including possible direct effects of the procedure, and whether there are differences in different study populations or differences based on blood pressure levels.

WHICH PATIENTS RESPOND BEST TO THIS PROCEDURE?

Although the Symplicity HTN-2 investigators report some predictors of increased reduction in blood pressure on multivariate analysis, including increased blood pressure at baseline and reduced heart rate at baseline, these are not specific enough to enable patient selection.

Interestingly, results from the expanded cohort of the Symplicity HTN-1 study found that patients on central sympatholytic agents such as clonidine had a greater reduction in blood pressure, although the reason for this is unclear.¹⁶ Identifying specific predictors of treatment success at baseline will be essential in future studies.

The earlier Symplicity trials and the ongoing Symplicity HTN-3 trial are in patients who have high blood pressure not responding to three or more antihypertensive drugs. The mean baseline systolic blood pressure in the Symplicity HTN-1 and HTN-2 trials was 178 mm Hg, and patients were taking an average of five antihypertensive drugs (Table 1). It is not known whether denervation will produce similar blood-pressure-lowering results across the spectrum of hypertension severity.

WHAT ARE THE LONG-TERM RESULTS OF DENERVATION?

Enthusiasm for the results from the Symplicity trials is tempered by concerns about the durability of the effects of the procedure, the need for better understanding of the impact of renal denervation on a wide array of pathophysiologic cascades leading to hypertension, and the effect on renal hemodynamics.

Antihypertensive efficacy has been reported to persist up to 2 years after the procedure,¹⁶ with recent unpublished data suggesting efficacy up to 3 years, but longer follow-up is needed to address whether these effects are finite.

Although reinnervation of afferent renal nerves has not been described, transplant models have shown anatomic regrowth of efferent nerves; the impact of this efferent reinnervation on blood pressure remains unclear. Experience from renal transplantation also shows that implanted kidneys that are “denervated” can still maintain fluid and electrolyte regulation.

Follow-up renal imaging in the Symplicity trials did not indicate renal artery stenosis at the sites of denervation in patients who underwent the procedure. Animal studies using the Symplicity catheter system showed renal nerve injury as evidenced by nerve fibrosis and thickened epineurium and perineurium, but no significant smooth muscle hyperplasia, arterial stenosis, or thrombosis by angiography or histology at 6 months.²⁰

WHAT ARE THE RISKS?

Adverse effects that were noted in the short term are detailed under discussion of the trials and in Table 2.

Long-term adverse events in the Symplicity HTN-2 trial that required hospitalization were reported in five patients in the denervation group and three patients in the control group (Table 2). These included transient ischemic attacks, hypertensive crises, hypotensive episodes, angina, and nausea.

Renal function was maintained for the duration of both trials, and details regarding eGFR change have been described above under the discussion of the trials.

Diffuse visceral pain at the time of the procedure is reported as an expected occurrence, managed with intravenous analgesic medications.

DOES SYMPATHETIC DENERVATION HAVE A ROLE IN OTHER CONDITIONS?

Interestingly, other sympathetically driven diseases, such as diabetes mellitus and polycystic ovary syndrome, may prove to be targets for this therapy in the future.²¹

Mahfoud et al²² conducted a pilot study in 37 patients with resistant hypertension undergoing renal denervation and 13 control patients. Fasting glucose levels declined from 118 ± 3.4 mg/dL to 108 ± 3.8 mg/dL after 3 months in the intervention group (P = .039), compared with no change in the control group. Insulin and C-peptide levels were also lower in the intervention group. The reported improvement in glucose metabolism and insulin sensitivity suggests that the beneficial effects of this procedure may extend beyond blood pressure reduction.

Brandt et al²³ reported regression of left ventricular hypertrophy and significantly improved cardiac functional parameters, including increase in ejection fraction and improved diastolic dysfunction, in a study of 46 patients who underwent renal denervation. This findings suggests a potential beneficial effect on cardiac remodeling.

Witkowski et al²⁴ reported lowering of blood pressure in 10 patients with refractory hypertension and obstructive sleep apnea who underwent renal denervation, which was accompanied by improvement of sleep apnea severity.

Ukena et al²⁵ reported reduction in ventricular tachyarrhythmias in two patients with congestive heart failure who had therapy-resistant electrical storm.

A recent pilot study in 15 patients with stage 3 and 4 chronic kidney disease (mean eGFR 31 mL/min/1.73 m²) showed significantly improved office blood pressure control up to 1 year, restoration of nocturnal dipping on 24-hour monitoring, as well as a nonsignificant trend towards increased hemoglobin levels and decreased proteinuria. No additional deterioration of renal function was reported in these patients (2 patients had renal function assessed up to 1 year).²⁶

Thus, the benefits of this procedure may extend to other diseases that have a common underlying thread of elevated sympathetic activity, by targeting the “sympathorenal” axis.²⁷

GUARDED OPTIMISM AND FUTURE DIRECTIONS

Given the well-known cardiovascular risks and health care costs associated with uncontrolled hypertension and the continued challenge that physicians face in managing it, novel therapies such as renal denervation may provide an adjunct to existing pharmacologic approaches.

While there is certainly cause for guarded optimism, especially with the striking blood pressure-lowering results seen in trials so far, it should be kept in mind that the mechanisms leading to the hypertensive response are complex and multifactorial, and further understanding of this therapy with long-term follow-up is needed. A comparison study with spironolactone, which is increasingly being used to treat resistant hypertension (in the absence of a diagnosis of primary aldosteronism)^28,29 would help to further establish the role of this procedure.

Studies of carotid baroreceptor stimulation via an implantable device have shown sustained reduction in blood pressure in patients with resistant hypertension. A study comparing this technique with renal denervation for efficacy and safety end points could be considered in the future.^30,31

The planned Symplicity HTN-3 study in the United States will be the largest trial to date, with a targeted randomization of more than 500 patients using strict enrollment criteria, including the use of maximally tolerated doses of diuretics and more focus on the use of ambulatory blood pressure monitoring and on the blinding of participants. This study will help further analysis of this technology in a more diverse population.^32,33

Future studies should be designed to clarify pathophysiologic mechanisms, patient selection criteria, effects on target organ damage, and efficacy in patients with chronic kidney disease, obesity, congestive heart failure, and in less severe forms of hypertension.

A CALL FOR PARTICIPANTS IN A CLINICAL TRIAL

The Departments of Cardiology and Nephrology and Hypertension at Cleveland Clinic are currently enrolling patients in the Symplicity HTN-3 trial. For more information, please contact George Thomas, MD ([email protected]), or Mehdi Shishehbor, DO, MPH ([email protected]), or visit www.symplifybptrial.com.

For patients with carotid artery stenosis, percutaneous intervention with stenting is as good as surgery (carotid endarterectomy). This was the major finding of the recently completed Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)¹—with some qualifications.

CREST is the latest in a series of clinical trials of treatment of carotid stenosis that have generated reams of numbers and much debate. The topic of surgery vs percutaneous intervention is a moving target, as techniques evolve and improve. We believe the CREST results are valuable and should help inform decisions about treatment in the “real world.”

In this article, we offer a critical review of CREST, with a careful evaluation of its methods, results, and conclusions.

AN EVOLVING FIELD

Despite improvements in diagnosis and management, stroke remains one of the leading causes of morbidity and death in the United States, with an annual incidence of 780,000 cases and 270,000 deaths.^2,3

Randomized trials of stenting have had mixed results, leading the Centers for Medicare and Medicaid Services (CMS) to adopt strict reimbursement policies. Currently, CMS reimburses for stenting only in symptomatic cases with at least 50% carotid artery stenosis. It also reimburses for stenting in asymptomatic cases in patients at high risk with 80% or greater stenosis, but only if the patients are enrolled in ongoing clinical trials or registries.

CREST compared stenting with endarterectomy and provided important insights into each approach.¹

BEFORE CREST

Endarterectomy is superior to medical therapy for symptomatic stenosis

First described in 1953, carotid endarterectomy became the most widely used invasive treatment for significant carotid stenosis.⁹ Several studies have described patient subsets that benefit from this procedure.

NASCET (the North American Symptomatic Carotid Endarterectomy Trial)¹⁰ assigned 2,226 patients with symptomatic stenosis (transient ischemic attack or stroke within the past 180 days) to medical management or endarterectomy.

Surgery was associated with a 65% lower rate of ipsilateral cerebral events in patients with 70% or greater stenosis.¹⁰ Surgery was also found to be superior in patients with moderate disease (50% to 69% stenosis), but the difference only approached statistical significance. In patients with stenosis of less than 50%, the outcomes were similar with endarterectomy and medical management.¹¹

ECST (the European Carotid Surgery Trial)¹² included a similar population of 3,024 patients. Those with high-grade disease (stenosis ≥ 80%) had significantly better outcomes with endarterectomy, but in those with stenosis less than 70%, surgery was no better than drug therapy.

Comment. NASCET and ECST taught us that endarterectomy is clearly superior to medical therapy in patients with severe symptomatic carotid disease. However, both trials excluded patients at high surgical risk, eg, those with severe coronary artery disease, kidney disease, or heart failure. Additionally, medical management was not aggressive by today’s standards in terms of control of blood pressure and hyperlipidemia, and this could have skewed the results in favor of carotid endarterectomy.

The case for carotid endarterectomy for asymptomatic stenosis

Endarterectomy has also been compared with drug therapy for asymp tomatic carotid artery stenosis in several trials.^13–15

ACAS (the Asymptomatic Carotid Atherosclerosis Study)¹⁵ assigned 1,662 patients who had no symptoms and had at least 60% carotid artery stenosis to endarterectomy or to medical management, and found a relative risk reduction of 53% in favor of surgery.¹⁵

The Veterans Affairs Cooperative Study Group¹⁴ corroborated these results in 444 patients with asymptomatic stenosis of greater than 50%. Endarterectomy was associated with a 61% lower risk of transient ischemic attack, transient monocular blindness, or stroke compared with medical therapy. However, there was no statistically significant difference in rates of stroke or death at 30 days.¹⁴

ACST (the Asymptomatic Carotid Surgery Trial),¹³ the largest study to compare carotid endarterectomy with drug therapy for asymptomatic stenosis, randomized 3,120 patients to surgery or drug therapy. The net 5-year risk of stroke was 6.4% with endarterectomy vs 11.8% with drug therapy (P < .0001). The rate of fatal stroke was also lower with endarterectomy: 2.1% vs 4.2% (P = .006).¹³

Comment. The results of these and other studies of endarterectomy vs medical therapy may not be applicable to current practice, since medical therapy has evolved and the risks with current drug therapy are likely much lower than seen in these trials, some of which began 2 decades ago. Another problem with interpreting these trials is that they excluded surgically “high-risk” patients, which limits the generalizability of the findings to this particular patient population.

The American Heart Association and the American Stroke Association have, on the basis of these trials, recommended carotid endarterectomy in patients with^7,8,16:

• Ipsilateral, symptomatic carotid artery stenosis of 70% to 99% (class I, level of evidence A)
• Symptomatic stenosis of 50% to 69%, depending on patient-specific factors such as age, sex, and comorbidities
• High-grade asymptomatic carotid stenosis, if the patients are carefully selected and the surgery is performed by surgeons with procedural morbidity and mortality rates of less than 3% (class I, level of evidence A).

While carotid endarterectomy is proven to be more efficacious than medical management in certain patient subsets, studies favoring surgery over medical therapy have been criticized because they excluded patients with significant comorbidities. In addition, surgery has been associated with significant cardiovascular events, wound complications, and cranial nerve damage, and it requires general anesthesia in most cases.^12,17–19 These and other factors spurred the development of less invasive, percutaneous approaches for patients with substantial comorbidities.

So far, several trials have investigated carotid angioplasty with or without stents and with or without devices to capture distal emboli. This interest set the stage for CREST.^20,21

Initial attempts at angioplasty without distal protection were not very successful. A meta-analysis of nonrandomized trials that included 714 patients from the initial 13 studies of angioplasty (with or without stenting) and 6,970 patients from 20 studies of carotid endarterectomy found angioplasty to be possibly associated with higher rates of stroke within 30 days of the procedure.²⁰

With improvements in technology, routine use of embolic protection devices, more experience, and better selection of patients, the outcome of carotid stenting has improved. In fact, a meta-analysis comparing stenting without an embolic protection device (26 trials with 2,357 patients) vs stenting with an embolic protection device (11 trials with 839 patients) showed that embolic protection led to significantly better outcomes with fewer strokes—outcomes arguably similar to those of carotid endarterectomy.²¹

SAPPHIRE (the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy trial)²² was the only completed US trial until CREST that compared carotid artery stenting with distal protection against surgery. It included 334 high-risk patients with either symptomatic stenosis of 50% or greater or asymptomatic stenosis of 80% or greater.

The results suggested that the outcomes with stenting with embolic protection were in fact similar to those of endarterectomy, with possibly fewer complications.²³ The benefit persisted up to 2 years.²²

The US Food and Drug Administration (FDA), on the basis of these data, approved the use of stenting with distal protection for high-risk patients, and the CMS reimburses for symptomatic stenosis of 50% or greater and for asymptomatic stenosis of 80% or greater as long as the patient is enrolled in a registry.

SPACE (the Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients trial),²⁴ conducted in Germany, included 1,214 patients with symptomatic stenosis of at least 50%. Results were similar in terms of the combined primary end point of stroke or death at 30 days. However, the results were not similar enough to prove that stenting is not inferior to surgery, according to preset study criteria.

EVA-3S (the Endarterectomy Versus Stenting in Patients With Symptomatic Severe Carotid Stenosis trial),²⁵ in France, evaluated 527 patients with symptomatic carotid disease (stenosis ≥ 60%), but was terminated early due to significantly higher rates of death or stroke at 30 days in the stenting group.

Comment. SPACE and EVA-3S have been widely criticized for not mandating the use of an embolic protection device (used in 27% of cases in SPACE and in 91.9% of cases in EVA-3S). Questions were also raised about the experience level of the operators who performed the carotid stenting: up to 39% of the primary operators involved in stent placement were trainees.²⁶ Also, myocardial infarction (MI), an important complication of carotid endarterectomy, was not included in the primary end point.

ICSS (the International Carotid Stenting Study)²⁷ compared stenting with endarterectomy in 1,713 patients with symptomatic carotid stenosis of greater than 50%. The primary end point was the rate of fatal or disabling stroke at 3 years.

An interim safety analysis at 120 days of follow-up showed the primary end point had occurred in 4.0% of stenting cases vs 3.2% of endarterectomy cases, a difference that was not statistically significant (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.77–2.11). However, the risk of any stroke was higher with stenting, with a rate of 7.7% vs 4.1% in the surgical group—a statistically significant difference (HR 1.92, 95% CI 1.27–2.89).

In a substudy of ICSS,²⁸ the investigators corroborated these findings, using magnetic resonance imaging to evaluate for new ischemic brain lesions periprocedurally. They found more new ischemic brain lesions in patients who underwent stenting than in patients who underwent surgery—a statistically significant finding.

Comment. ICSS had limitations: eg, it included only patients with symptoms, and the training for the stenting procedure was not standardized. Furthermore, the use of embolic protection devices was not mandated in stenting procedures.

Because of the controversial and incongruous findings of the above trials, there has been much anticipation for further large, appropriately conducted, randomized controlled trials such as CREST.

CREST STUDY DESIGN

CREST was a prospective, multicenter randomized controlled trial with blinded end point adjudication. Assignment to stenting or surgery occurred in a one-to-one fashion, and patients were stratified by medical center and symptomatic status.

Conducted at 108 sites in the United States and nine sites in Canada, CREST was supported by a grant from the National Institutes of Health and by the manufacturer of the catheter and stent delivery and embolic protection systems. The manufacturer’s representative held a nonvoting position on the executive committee and reviewed the manuscript of the results before submission.

CREST included patients with or without symptoms

CREST was initially designed to compare carotid artery stenting vs carotid endarterectomy in patients with symptoms, but enrollment was later extended to patients without symptoms.

Patients with symptoms were included if they had stenosis of at least 50% on angiography, at least 70% on ultrasonography, or at least 70% on computed tomographic angiography or magnetic resonance angiography if stenosis on ultrasonography was 50% to 69%. Carotid artery stenosis was considered symptomatic if the patient had a transient ischemic attack, amaurosis fugax, or minor disabling stroke in the hemisphere supplied by the target vessel within 180 days of randomization.

Patients without symptoms were eligible if they had at least 60% stenosis on angiography, at least 70% stenosis on ultrasonography, or at least 80% stenosis on computed tomographic angiography or magnetic resonance angiography if the stenosis was 50% to 69% on ultrasonography.

Other eligibility criteria included favorable anatomy and clinical stability for both stenting and surgical procedures.

Exclusion criteria were evolving stroke, history of major stroke, chronic or paroxysmal atrial fibrillation on anticoagulation therapy, MI within the previous 30 days, and unstable angina.

Patients undergoing stenting received aspirin and clopidogrel (Plavix) before and up to 30 days after the procedure. Continuation of antiplatelet therapy was recommended beyond 1 month.

Patients undergoing endarterectomy received aspirin before surgery and continued to receive aspirin for at least 1 year.

Alternatives to aspirin in both groups were ticlopidine (Ticlid), clopidogrel, or aspirin with extended-release dipyridamole (Aggrenox).

End points: Stroke, MI, death

The primary end point was a composite of periprocedural clinical stroke (any type), MI, or death, and of ipsilateral stroke up to 4 years after the procedure. Secondary analyses were also planned for evaluation of treatment modification by age, symptom status, and sex.

Stroke was defined as any acute neurologic ischemic event lasting at least 24 hours with focal signs and symptoms.

Two separate definitions were applied to distinguish major stroke from nonmajor stroke. Major stroke was defined as a National Institutes of Health Stroke Scale (NIHSS) score greater than 9 or records suggesting that the event was a disabling stroke if admitted to another facility. Nonmajor stroke included an event that did not fit these criteria. The stroke review process was initiated with a significant neurologic event, a positive transient ischemia attack or stroke questionnaire, or a two-point or greater increase in the NIHSS score.

MI was defined as a combination of an elevation of cardiac enzymes to at least twice the laboratory upper limit of normal, as well as clinical signs suggesting MI or electrocardiographic evidence of ischemia.²⁹

Stroke was adjudicated by two independent neurologists, and MI was adjudicated by two independent cardiologists blinded to treatment group assignment.

The Rankin scale, the transient ischemic attack and stroke questionnaire, and the Medical Outcomes Survey were also used to assess for disability and quality of life in long-term follow-up.

Intention-to-treat analysis

Intention-to-treat survival analysis was used along with time-to-event statistical modeling with adjustment for major baseline covariates. Differences in outcomes were assessed, and a noninferiority analysis was performed. Kaplan-Meier estimates were constructed of the proportion of patients remaining free of the composite end point at 30 days, 6 months, 1 year, and annually thereafter, and of the associated confidence intervals. The hazard ratios between groups were estimated after adjustment for important covariates.

Most patients enrolled were available for analysis

From December 2000 to July 2008, 2,522 patients were enrolled; 1,271 were assigned to stenting, and 1,251 were assigned to surgery. After randomization, 2.8% of the patients assigned to stenting withdrew consent, 5.7% underwent surgery, and 2.6% were lost to follow-up. Of those assigned to surgery, 5.1% withdrew consent, 1.0% underwent stenting, and 3.8% were lost to follow-up.

A ‘conventional-risk’ patient population

The trial sought to include a “conventional-risk” patient population to make the study more applicable to real-world practice. The mean age was 69 years in both groups. Of the 2,522 patients enrolled:

• 35% were women
• 47% had asymptomatic carotid disease
• 86% had carotid stenosis of 70% or greater
• 86% had hypertension
• 30% had diabetes mellitus
• 83% had hyperlipidemia
• 26% were current smokers
• 42% had a history of cardiovascular disease
• 21% had undergone coronary artery bypass grafting surgery.

The only statistically significant difference in measured baseline variables between the two treatment groups was a slightly higher rate of dyslipidemia in the group undergoing surgery.

The interventionalists and surgeons were highly experienced

Operators performing stenting underwent a lead-in phase of training, with close supervision and scrutiny before eligibility. Of patients undergoing stenting, 96.1% also received an embolic protection device. Antiplatelet therapy was continued in 99% of the patients.

The surgeons performing endarterectomy were experienced and had documented low complication rates. General anesthesia was used in 90% of surgical patients. Shunts were used during surgery in 57%, and patches were used in 62%. After endarterectomy, 91% of the patients received antiplatelet therapy.

CREST STUDY RESULTS: STENTING WAS AS GOOD AS SURGERY

Periprocedural outcomes

• Stroke, MI, or death: 5.2% with stenting vs 4.5% with surgery, HR 1.18, 95% CI 0.82–1.68, P = .38
• Stroke: 4.1% vs 2.3%, HR 1.79, 95% CI 1.14–2.82, P = .01
• 
  Major ipsilateral stroke: 0.9% vs 0.3%, HR 2.67, 95% CI 0.85–8.40, P = .09.
• MI: 1.1% vs 2.3%, HR 0.50, 95% CI 0.26–0.94, P = .03
• Cranial nerve palsy: 0.3% vs 4.8%, HR 0.07, 95% CI 0.02–0.18, P < .0001 (Table 2).

Outcomes at 4 years

• 

  Brott TG, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363:11–23. Copyright 2010, Massachusetts Medical Society. All rights reserved.

  The primary end point (periprocedural stroke, MI, or death, or ipsilateral stroke within 4 years after the procedure): 7.2% with stenting vs 6.8% with surgery, HR 1.11, 95% CI 0.81–1.51, P = .51. A Kaplan-Meier analysis showed similar findings with statistically similar outcomes (Figure 2).
• Ipsilateral stroke: 2.0% vs 2.4%, HR 0.94, 95% CI 0.50–1.76, P = .85.

The primary outcome was analyzed for interactions of baseline variables, and no effect was detected for symptomatic status or sex. There was a suggestion of an interaction with age, with older patients (over age 70) benefiting more from endarterectomy.

Quality-of-life indices showed that both major and minor strokes were likely to produce long-term physical limitations, with minor stroke associated with worse mental and physical health at 1 year. The effect of periprocedural MI on long-term physical and mental health was less certain. The increased incidence of cranial nerve palsy noted with endarterectomy has been found before and has had no effect on quality of life.

WHAT DO THE CREST FINDINGS MEAN?

CREST is the largest trial to date to compare stenting and surgery. It is an important addition to the literature, not only because of its size, but also because it focused on a real-world patient population. For this reason, its results are more applicable to patients seen in primary care clinics, ie, with peripheral vascular disease, coronary artery disease, diabetes mellitus, hypertension, and smoking.

As noted, previous studies of endarterectomy had strict inclusion and exclusion criteria, which selected against patients at high surgical risk. Therefore, the CREST findings are of greater relevance when comparing stenting and endarterectomy.

Periprocedural and long-term neurologic outcomes

CREST showed similar findings for the composite end point of periprocedural stroke, death, or MI (ie, within 30 days of the procedure) and long-term stroke, establishing similar outcomes in patients undergoing stenting and surgery.

However, an analysis of the individual components of the composite end point showed significant differences between the two treatments. The risk of ipsilateral periprocedural stroke was higher with stenting; these events were defined as nonmajor by NIHSS criteria. The risk of contralateral stroke was similar and low with each treatment.

While the increased risk of periprocedural ipsilateral stroke was not synonymous with an increased risk of major stroke, post hoc analysis showed that any stroke was associated with decreased physical and mental health at 1 year. Therefore, patients who had even a minor stroke did worse from a physical and mental standpoint, a finding that argues for the superiority of surgery in selected patients at risk of periprocedural stroke.

If periprocedural stroke is excluded, the risk of long-term ipsilateral stroke was similar for each treatment, and extremely low (2% for stenting, 2.4% for surgery). Despite this, given the importance of periprocedural minor and major stroke, better predictive models are needed to identify patients at risk of procedural neurologic events. These prediction models will allow better patient selection.

The CREST data and medical therapy

The rates of stroke in this trial were similar to those observed with current medical treatment (approximately 1% per year), especially for patients with asymptomatic disease. Such findings introduce fresh controversy in the necessity of performing either procedure for this patient subset and may lead to further studies evaluating current medical therapy vs intervention.

Periprocedural myocardial infarction

Vascular surgery has long been associated with high cardiovascular risk, especially an increased risk of periprocedural MI.³⁰ Findings from CREST provide further evidence of the risk of MI with endarterectomy in a real-world patient population. Given the evidence of a strong correlation between periprocedural cardiac enzyme elevations and adverse outcomes, the increased incidence of periprocedural MI is worrisome.³¹ As with risk assessment for periprocedural stroke, better predictive models are needed for patients at risk of cardiovascular events during endarterectomy.

Procedural complications

Carotid endarterectomy entails incisions in the neck with disruption of tissue planes, as opposed to catheter entry site wounds with stenting. The more invasive nature of endarterectomy thus carries a higher risk of wound complications. In fact, in the NASCET trial, the risk of wound complications was 9.3%.^10,19 In CREST, surgery carried a higher risk of wound complications compared with stenting (42 vs 0 cases), although stenting involved more periprocedural transfusions, presumably due to retroperitoneal bleeding in four patients.

Use of general anesthesia is also associated with adverse outcomes.^17,18 In CREST, 90% of endarterectomy procedures required general anesthesia, whereas none of the stenting procedures required this.

Cranial nerve palsy is an often overlooked but real complication after these procedures. Cranial nerve palsies can lead to vocal, swallowing, and sensory problems that can have a transient or permanent impact on quality of life. In CREST, as in EVA-3S, SAPPHIRE, and ICSS, this risk was substantially higher with surgery,^23,25,27 although the long-term consequences of these palsies were not found to affect quality of life at 1 year of follow-up.

HOW CREST FINDINGS COMPARE WITH PREVIOUS STUDIES

Patients in CREST enjoyed overall better outcomes than in previous studies. In earlier trials of surgery vs medical therapy, the rates of adverse outcomes were higher than in CREST. In NASCET, the risk of ipsilateral stroke was 9% with surgery, with 2.5% being fatal or disabling strokes.¹⁰ In the ECST, rates of major stroke or death with endarterectomy were 7.0% within 30 days of surgery and 37.0% at a mean follow-up of 6.1 years.¹²

In earlier studies of surgery vs stenting, outcomes at 30 days were also substantially worse than those in CREST. In the EVA-3S trial, the 30-day incidence of stroke or death was 3.9% after surgery and 9.6% after stenting. These findings were similar at 6 months in EVA-3S, with a 6.1% rate of adverse events after surgery and 11.7% after stenting.²⁵ In the SAPPHIRE trial, the cumulative incidence of stroke and death at 1 year was 21.4% for surgery and 13.6% for stenting.²³

Overall, the CREST results show better outcomes than in previous trials. This may be due to improvements in technical aspects of the interventions and to more aggressive drug therapy. Also, because of the high number of patients enrolled in CREST, surgeons and interventionalists were required to meet eligibility criteria, which could have contributed to the improved outcomes.³²

CREST was also unique in that stenting was done with an embolic protection device whenever possible, and this also likely had an impact on outcomes.

CREST vs ICSS

CREST and ICSS, published within a few months of each other, seem to have arrived at entirely different conclusions. As both studies are well-designed randomized controlled trials, these distinct results have yielded much controversy. However, closer scrutiny sheds light as to why the results may be different.

While ICSS focused only on patients with symptoms, CREST also included those without symptoms. The difference in patient populations is itself enough to account for the different outcomes.

Also, the interim analysis of ICSS was at 120 days, which makes periprocedural events a more dominant factor in outcomes, whereas these events likely do not last into the long term, as was the case in CREST. Analysis of the ICSS data at a later follow-up date may show results more similar to those of CREST.

The design of ICSS was also different than CREST. In ICSS, the use of an embolic protection device in stenting was not mandated, and the study lacked a lead-in phase of intensive training for those performing stenting. Furthermore, MI was adjudicated only when clinically recognized, which is different than the more rigorous method used in CREST.

Yet despite these differences, CREST and ICSS shed light on a controversial area of carotid stenosis management, and both studies boasted low rates of periprocedural complications. Clinicians should keep in mind the inclusion criteria and the technical specificities of these trials in order to explain to patients the risks and benefits of stenting and surgery, and to arrive at a decision together.

Limitations

The results of CREST should also be reviewed carefully due to a number of limitations. The study began in 2000 with symptomatic patients only, and began enrolling asymptomatic patients in 2005, so that the methodology of the study was changed midway. However, the investigators performed a subgroup analysis to distinguish between outcomes of the symptomatic and the asymptomatic groups and found no statistical interaction for the primary end point based on symptom status.

Despite careful patient selection, many of the predictors of adverse outcomes with stenting, such as lesion length, level of calcification, and lesion location, were not accounted for in the earlier days of enrollment. This may have had an impact on the incidence of stroke in patients enrolled in the early years of the trial. We await the analysis of predictors of perioperative stroke from CREST.

TAKE-HOME POINTS AND FUTURE DIRECTIONS

The CREST findings show that outcomes with stenting are similar to those with surgery in both the short term and the long term, and that the choice of management should be individualized. Each patient’s risk of MI and stroke should be considered based on a variety of factors, including the severity of coronary artery disease, the length of the carotid lesion, the level of calcification, the location of the lesion, and aortic atheroma. The treatment should be selected after also taking into account the patient’s preference and the available expertise, and only after a comprehensive discussion with the patient.