PAD in Focus

A Need for Comparative Randomized Data in the DCB Era

Peripheral artery disease is an endemic problem that affects millions of people around the globe. Peripheral artery disease leads to significant morbidity and mortality and is a strong marker for increased incidence of MI and stroke, the main causes of death in most of these patients.

Patients with PAD should be first treated with very aggressive risk-modification therapies such as a supervised exercise program, smoking cessation, antiplatelet agents, statins and optimal diabetes management. When these measures are not sufficient to restore good functional status or when PAD is advanced to the point of critical limb ischemia, revascularization therapies become important to improve quality of life and reduce amputation and its dreadful consequences.

The DCB Solution

Endovascular therapy for PAD has increased exponentially in the past few years, surpassing surgical interventions, fueled predominantly by an increased awareness of the problem and the introduction of several tools needed to treat successfully complex disease. Although excellent acute procedural results have been obtained with bare-metal stenting of the femoropopliteal arteries, and recently with a no-stent strategy using atherectomy, the long-term results of these techniques have been generally disappointing, with a high rate of patency loss and need for repeat revascularization.

Also, despite advances in stent technology and likely greater durability of these scaffolds, there is a visible movement against permanent metal implants in highly mobile vessels such as the femoropopliteal artery that are subjected to various forces.

The introduction of drug-coated balloons offered an elegant solution to the problem of restenosis. Several randomized studies against percutaneous transluminal angioplasty (PTA) have consistently shown superior results in the outcome of patency with the use of DCB. In addition, target lesion revascularization was significantly reduced with DCB in most of these studies. Although mortality, quality of life, Rutherford category and ankle-brachial index were statistically similar at 1-year follow-up with DCB vs. PTA, there was a lower need for revascularization in the DCB arm.

Nicolas W. Shammas

There are currently two approved DCBs in the United States: Lutonix DCB (C.R. Bard) and IN.PACT Admiral (Medtronic Vascular). The premarket approval application for the Stellarex DCB (Spectranetics) was submitted to the FDA in November; the company expects a decision in the second half of 2017. A fourth DCB, Ranger (Boston Scientific), is currently in pivotal trial testing. All four DCBs use paclitaxel as the active antiproliferative drug, but they are different in dosing of paclitaxel (2-3.5 µg/mm2), use of excipients (polysorbate and sorbitol, urea, polyethylene glycol and citrate ester) and coating technology. It is clear that all DCBs are not created equal in their manufacturing process and are different in the extent of paclitaxel drug transfer to the vessel wall. Therefore, one would expect differences in their effectiveness and a “no-class effect” could be speculated.

Randomized trials have shown that patency is improved in all DCBs, but the magnitude of the difference seems to be larger with the IN.PACT and Stellarex balloons vs. Lutonix compared with PTA. Further, the long-term data from these trials indicated a higher magnitude of patency loss at 2-year follow-up with Lutonix compared with IN.PACT vs. PTA.

Difficult Comparison

Despite the temptation to declare a winner (or a no-class effect) based on a comparison of DCB findings across the randomized trials, a word of caution is warranted. DCB trials are performed by different operators with different inclusion and exclusion criteria and different definitions of endpoints.

One of the most significant differences among these trials is the degree of calcification and how it was defined. The percentage of patients identified as having severe calcification varied greatly (see Figure). Calcium may potentially be an impediment for drug diffusion; transport across the vessel wall and severe calcium has been associated with worse outcomes.

Also, in the ILLUMENATE pivotal trial, severe calcium was defined as “radiopacities noted on both sides of the arterial wall extending more than 1 cm in length prior to contrast injection or digital subtraction,” whereas in the IN.PACT SFA trial, it was defined by a core laboratory as “calcium visible along both sides of the arterial wall, covers 2 cm or greater of the target lesion area, encompasses greater than 50% of the total target lesion treatment area by visual estimate and/or the calcium is circumferential (360 degrees in nature on both sides of the vessel lumen extending 2 cm or greater on a single [anteroposterior] view), or classified as exophytic calcification which significantly impedes blood flow in the vessel.”

All definitions of severe calcium, however, included bilateral calcium (> 180°) as a common denominator, but different lengths of calcium were considered. Small studies have suggested that bilateral calcium is the dominant predictor of outcome irrespective of length, but this has not been validated in prospective, larger studies.

Furthermore, procedural success was defined differently among the pivotal trials. In the LEVANT 2 trial, procedural success was defined as a residual narrowing of 30% without major adverse events, whereas in IN.PACT SFA, it was 50% in the nonstented vessels and 30% in the stented ones, and in ILLUMENATE, it was 50% with no major adverse events.

Finally, demographic and angiographic differences were noted among the trials, including percent of females, chronic total occlusions, lesion length, presence of diabetes and renal insufficiency, the implications of which are unclear.

‘No-class Effect Conclusion Should Be Put on Hold’

As of today, no head-to-head data exist that compare DCBs to conclusively say that a no-class effect is present. Two ongoing trials are comparing Lutonix with IN.PACT: the Compare I Pilot Study in Germany and Austria and the HEROES trial in the United States. Given the smaller number of patients these trials are enrolling, they must be considered pilot or exploratory studies, but may give some important insights into the differences that exist among DCBs.

Pivotal trials of DCBs included shorter lesions (< 10 cm) and less severe calcium (except ILLUMENATE, but this was likely due to the definition of severe calcium in that trial). Also, patients with flow-limiting dissection or high residual narrowing with predilation were excluded. By contrast, data from several registries, including IN.PACT Global, Lutonix Global, ILLUMENATE Global, the Lutonix SAFE-DCB U.S. registry and the long-lesion DCB registries — Lutonix EU Long Lesion and IN.PACT SFA-Long — are now available. These registries included real-world characteristics such as longer lesion length, higher percentage of CTOs, in-stent restenosis, popliteal arteries, patients with CLI, and more bailout stenting. Furthermore, in the SAFE-DCB registry, approximately half the vessels were prepped with atherectomy or specialized balloons.

At 1 year, freedom from TLR was 94.1% in the Lutonix Global, 92.5% in IN.PACT Global and 93.8% in ILLUMENATE Global registries. Also, primary patency was 82.5% in the Lutonix Global registry (vs. 73.5% in LEVANT 2) despite more complex disease in this registry. In SAFE-DCB, preliminary data showed freedom from TLR at 6 months to be 95.7%. Although several explanations can be offered for the differences in outcomes between randomized trials and registries, these data warrant caution in concluding that a no-class effect is present without the benefit of the doubt of well-conducted randomized clinical trials.

In conclusion, there are clear manufacturing differences among DCBs including paclitaxel dosing, excipient types and coating technology. Randomized trials of DCB compared with PTA in treating de novo femoropopliteal arteries have shown better patency and freedom from TLR with DCB. Although the magnitude of the benefit appears different among the randomized trials over time, real-world data with more complex disease do not support the presence of major differences among DCB. At this time, a no-class effect conclusion should be put on hold until ongoing randomized comparative trials among DCB are complete.

Disclosure: Shammas reports consulting for and receiving research and educational grants from Boston Scientific and C.R. Bard.

Peripheral artery disease is an endemic problem that affects millions of people around the globe. Peripheral artery disease leads to significant morbidity and mortality and is a strong marker for increased incidence of MI and stroke, the main causes of death in most of these patients.

Patients with PAD should be first treated with very aggressive risk-modification therapies such as a supervised exercise program, smoking cessation, antiplatelet agents, statins and optimal diabetes management. When these measures are not sufficient to restore good functional status or when PAD is advanced to the point of critical limb ischemia, revascularization therapies become important to improve quality of life and reduce amputation and its dreadful consequences.

The DCB Solution

Endovascular therapy for PAD has increased exponentially in the past few years, surpassing surgical interventions, fueled predominantly by an increased awareness of the problem and the introduction of several tools needed to treat successfully complex disease. Although excellent acute procedural results have been obtained with bare-metal stenting of the femoropopliteal arteries, and recently with a no-stent strategy using atherectomy, the long-term results of these techniques have been generally disappointing, with a high rate of patency loss and need for repeat revascularization.

Also, despite advances in stent technology and likely greater durability of these scaffolds, there is a visible movement against permanent metal implants in highly mobile vessels such as the femoropopliteal artery that are subjected to various forces.

The introduction of drug-coated balloons offered an elegant solution to the problem of restenosis. Several randomized studies against percutaneous transluminal angioplasty (PTA) have consistently shown superior results in the outcome of patency with the use of DCB. In addition, target lesion revascularization was significantly reduced with DCB in most of these studies. Although mortality, quality of life, Rutherford category and ankle-brachial index were statistically similar at 1-year follow-up with DCB vs. PTA, there was a lower need for revascularization in the DCB arm.

Nicolas W. Shammas

There are currently two approved DCBs in the United States: Lutonix DCB (C.R. Bard) and IN.PACT Admiral (Medtronic Vascular). The premarket approval application for the Stellarex DCB (Spectranetics) was submitted to the FDA in November; the company expects a decision in the second half of 2017. A fourth DCB, Ranger (Boston Scientific), is currently in pivotal trial testing. All four DCBs use paclitaxel as the active antiproliferative drug, but they are different in dosing of paclitaxel (2-3.5 µg/mm2), use of excipients (polysorbate and sorbitol, urea, polyethylene glycol and citrate ester) and coating technology. It is clear that all DCBs are not created equal in their manufacturing process and are different in the extent of paclitaxel drug transfer to the vessel wall. Therefore, one would expect differences in their effectiveness and a “no-class effect” could be speculated.

PAGE BREAK

Randomized trials have shown that patency is improved in all DCBs, but the magnitude of the difference seems to be larger with the IN.PACT and Stellarex balloons vs. Lutonix compared with PTA. Further, the long-term data from these trials indicated a higher magnitude of patency loss at 2-year follow-up with Lutonix compared with IN.PACT vs. PTA.

Difficult Comparison

Despite the temptation to declare a winner (or a no-class effect) based on a comparison of DCB findings across the randomized trials, a word of caution is warranted. DCB trials are performed by different operators with different inclusion and exclusion criteria and different definitions of endpoints.

One of the most significant differences among these trials is the degree of calcification and how it was defined. The percentage of patients identified as having severe calcification varied greatly (see Figure). Calcium may potentially be an impediment for drug diffusion; transport across the vessel wall and severe calcium has been associated with worse outcomes.

Also, in the ILLUMENATE pivotal trial, severe calcium was defined as “radiopacities noted on both sides of the arterial wall extending more than 1 cm in length prior to contrast injection or digital subtraction,” whereas in the IN.PACT SFA trial, it was defined by a core laboratory as “calcium visible along both sides of the arterial wall, covers 2 cm or greater of the target lesion area, encompasses greater than 50% of the total target lesion treatment area by visual estimate and/or the calcium is circumferential (360 degrees in nature on both sides of the vessel lumen extending 2 cm or greater on a single [anteroposterior] view), or classified as exophytic calcification which significantly impedes blood flow in the vessel.”

All definitions of severe calcium, however, included bilateral calcium (> 180°) as a common denominator, but different lengths of calcium were considered. Small studies have suggested that bilateral calcium is the dominant predictor of outcome irrespective of length, but this has not been validated in prospective, larger studies.

Furthermore, procedural success was defined differently among the pivotal trials. In the LEVANT 2 trial, procedural success was defined as a residual narrowing of 30% without major adverse events, whereas in IN.PACT SFA, it was 50% in the nonstented vessels and 30% in the stented ones, and in ILLUMENATE, it was 50% with no major adverse events.

Finally, demographic and angiographic differences were noted among the trials, including percent of females, chronic total occlusions, lesion length, presence of diabetes and renal insufficiency, the implications of which are unclear.

PAGE BREAK

‘No-class Effect Conclusion Should Be Put on Hold’

As of today, no head-to-head data exist that compare DCBs to conclusively say that a no-class effect is present. Two ongoing trials are comparing Lutonix with IN.PACT: the Compare I Pilot Study in Germany and Austria and the HEROES trial in the United States. Given the smaller number of patients these trials are enrolling, they must be considered pilot or exploratory studies, but may give some important insights into the differences that exist among DCBs.

Pivotal trials of DCBs included shorter lesions (< 10 cm) and less severe calcium (except ILLUMENATE, but this was likely due to the definition of severe calcium in that trial). Also, patients with flow-limiting dissection or high residual narrowing with predilation were excluded. By contrast, data from several registries, including IN.PACT Global, Lutonix Global, ILLUMENATE Global, the Lutonix SAFE-DCB U.S. registry and the long-lesion DCB registries — Lutonix EU Long Lesion and IN.PACT SFA-Long — are now available. These registries included real-world characteristics such as longer lesion length, higher percentage of CTOs, in-stent restenosis, popliteal arteries, patients with CLI, and more bailout stenting. Furthermore, in the SAFE-DCB registry, approximately half the vessels were prepped with atherectomy or specialized balloons.

At 1 year, freedom from TLR was 94.1% in the Lutonix Global, 92.5% in IN.PACT Global and 93.8% in ILLUMENATE Global registries. Also, primary patency was 82.5% in the Lutonix Global registry (vs. 73.5% in LEVANT 2) despite more complex disease in this registry. In SAFE-DCB, preliminary data showed freedom from TLR at 6 months to be 95.7%. Although several explanations can be offered for the differences in outcomes between randomized trials and registries, these data warrant caution in concluding that a no-class effect is present without the benefit of the doubt of well-conducted randomized clinical trials.

In conclusion, there are clear manufacturing differences among DCBs including paclitaxel dosing, excipient types and coating technology. Randomized trials of DCB compared with PTA in treating de novo femoropopliteal arteries have shown better patency and freedom from TLR with DCB. Although the magnitude of the benefit appears different among the randomized trials over time, real-world data with more complex disease do not support the presence of major differences among DCB. At this time, a no-class effect conclusion should be put on hold until ongoing randomized comparative trials among DCB are complete.

Disclosure: Shammas reports consulting for and receiving research and educational grants from Boston Scientific and C.R. Bard.