Cardiovascular disease associated with atherosclerosis is a condition mainly associated with a thickening of the artery wall and the eventual blockage of blood flow in an artery due to fatty deposits and plaque formation. When cardiovascular disease is brought to mind, the heart is what people think of most; however, although the heart is the predominant organ affected by cardiovascular disease associated with atherosclerosis, the same condition can also affect blood flow to the kidneys, brain and legs. When considered together, cardiovascular disease is easily the number one cause of death in the industrialised world.
The Heart – Cardiovascular Arterial Disease
Advanced cases of cardiovascular disease associated with atherosclerosis may be associated with chest pain on exertion that settles within a few minutes of rest (angina). However, if any of the arteries supplying the heart (coronary arteries) become completely blocked, the portion of the heart muscle that is deprived of blood may die, causing a heart attack (myocardial infarction). Small heart attacks, where a small portion of heart tissue is denied blood flow, can cause permanent impairment of the performance of the heart, ultimately affecting lifestyle and lifespan. Large heart attacks can obviously cause immediate death.
The Legs – Peripheral Arterial Disease
Atherosclerosis affecting the arteries in the legs may be first associated with a cramping pain in the leg muscles upon exertion that will settle after a rest for a few minutes (intermittent claudication). The pain is a result of the leg muscles not getting enough blood (and hence oxygen) to compensate for the physical effort that the muscles have undertaken. More advanced atherosclerosis may cause constant pain at rest, ulceration of the lower leg and even gangrene in the toes and feet (critical limb ischaemia), leading to amputation. Patients undergoing amputation then face a significantly shortened lifespan due to lack of mobility and consequent inability to exercise.
A General History of Interventional Cardiovascular Device Therapy
Over the last 30 years, great advances have been made in the interventional treatment of cardiovascular disease; however, to date there have been only three ‘successful and sustainable’ device platforms for the treatment of atherosclerosis. The first successful and sustainable device platform for the treatment of atherosclerosis was established in 1977, with the performance of the first balloon angioplasty case by Andreas Gruentzig. As a result, the balloon angioplasty procedure developed and gained critical mass and prominence in the 1980s, providing the initial procedure base for the modern-day interventional cardiologist. Although more than 30 years old, balloon angioplasty is still a commonly performed procedure, especially in the peripheral vasculature. The advantage of balloon angioplasty is the simplicity of the procedure, the flexibility and deliverability of the catheters through difficult anatomy and the fact that it is all performed through a small puncture in the groin area. The disadvantages are the inability to prevent the vessel from mechanical recoil shortly after the procedure and the inability to prevent tissue in-growth, both of which contribute to the requirement for repeat procedures. In addition, in the coronary circulation, balloon angioplasty carries a single-digit incidence of ‘acute closure’, a situation where the coronary vessel will thrombose (form a blood clot) and close suddenly within hours of the initial procedure.
In the 1990s, a second successful and sustainable device platform for the treatment of atherosclerosis emerged: the bare-metal stent (BMS). This platform was successful because it was relatively easy to deploy (delivered with an angioplasty balloon) and could prevent the area that was opened with a balloon from recoiling back down post-procedure, and because improved techniques of stent deployment virtually eliminated the incidence of acute closure. However, BMS were still unable to prevent tissue in-growth.
With the turn of the millennium, a third successful and sustainable device platform for the treatment of atherosclerosis was introduced: the drug-eluting stent (DES). Similar to the BMS, this device was successful because it was easy to deploy (delivered with an angioplasty balloon) and could prevent the area that was opened with a balloon from recoiling back down after the procedure, and because improved techniques of stent deployment virtually eliminated the incidence of acute closure. However, DES were also superior to BMS in terms of their ability to prevent tissue in-growth in most situations. This additional advantage helped propel DES to become what is now the second-largest medical device product (by revenue) in the world.
At the cusp of the second decade of the 21st century there are three successful and sustainable platforms: balloon angioplasty, BMS and DES. Can drug-eluting balloons (DEBs) become the fourth successful and sustainable device platform for the treatment of atherosclerosis? Will the next decade add another important platform to the armamentarium of interventionalists?
At this point we can say it is a distinct possibility. DEBs represent a novel treatment option for atherosclerosis in both the coronary and peripheral arteries. The DEB is a regular angioplasty balloon coated with a drug that is usually embedded in a matrix coating, using a hydrophilic spacer to allow the drug to be effectively released when the balloon is expanded in apposition with the vessel wall. The drug is then absorbed in the vessel wall and prevents the tissue in-growth that is normally the consequence of either balloon or stent expansion in an artery.
There are several reasons why DEBs have the potential to become the fourth successful and sustainable device platform in the history of intervention:
- All successful and sustainable platforms have been balloon-based: DEBs are also balloon-based. In addition, plain old balloon angioplasty is still the standard of care in peripheral vascular anatomies such as femoropopliteal (fempop, ~70% utilisation as definitive therapy), below-the-knee (BTK, ~90% utilisation as definitive therapy) and dialysis shunts (>95% utilisation as definitive therapy).
- Access. Physicians need the ability to guide the device to the target area in the artery in order to perform the treatment. DEBs perform as well as standard balloon angioplasty catheters and can reach the same target areas in an artery. There is no decrease in performance. Therefore, DEBs can access and deliver a therapy and drug to places that stents cannot.
- Technique. DEBs do not require special talent or significant physician training. The method of deployment for a DEB is similar to the methods of deployment for a standard balloon angioplasty catheter. Physicians are required to pre-dilate or open the lesion first with a standard balloon angioplasty catheter. The DEB will then be used to post-dilate, deliver the drug to the vessel wall and secure a pristine result.
- Homogeneous drug delivery. DEBs deliver the drug homogeneously over 100% of the surface area of the balloon that is in contact with the vessel wall. DES typically delivers drug over a surface area of ≤20%.
- An implant is not left behind. Standard balloon angioplasty catheters also leave nothing behind, but they do not address tissue in-growth. A DES addresses tissue in-growth in most cases, but leave an implant and in many cases a polymer coating that can cause long-term inflammation and late stent thrombosis (a life-threatening condition where arterial inflammation leads to clot formation and a sudden blockage in the artery).
- Potential for shortened antiplatelet therapy. In theory, nothing is left behind to cause chronic inflammation, so antiplatelet therapies used at length after DES stent therapy may be shortened. This has a positive impact on both cost and quality of life.
- Clinical data. Randomised trials conducted with prototypes of paclitaxel DEBs have focused on areas where the current therapeutic platforms do not offer satisfactory solutions, such as coronary in-stent restenosis (where there is tissue growth inside the stent) or the treatment of the superficial femoral arteries. These randomised trials have shown consistent and significant benefits for the DEB arm.1–7 Future trials will provide additional data in these areas and also investigate the effectiveness of DEBs in coronary bifurcations, coronary small vessels, haemodialysis shunts and lesions BTK.
The Invatec IN.PACT™ Platform
IN.PACT™ Admiral, IN.PACT Pacific, IN.PACT Amphirion and IN.PACT Falcon represent four DEB platforms that Invatec has introduced to the market.
Invatec is now the only company with a DEB on four product platforms targeting four different anatomies: the coronaries, the superficial femoral artery (SFA), the fempop and arteries BTK. IN.PACT features FreePac™, a proprietary matrix coating with a hydrophilic spacer that frees and separates Paclitaxel molecules and facilitates their absorption into the wall of the artery. The specific hydrophilic spacer is ‘urea’, a non-toxic ubiquitous compound that is naturally produced by the body. The dose of paclitaxel on the balloon is 3μg/mm2 of balloon surface. The FreePac coating was developed in close collaboration with the researchers who pioneered DEB therapy: Ulrich Speck, PhD, from the Department of Radiology at Charite Mitte, Berlin, and Bruno Scheller, MD, from the Department of Internal Medicine at University Hospital Homburg/Saar.
Invatec is currently investing heavily in well-conducted randomised scientific trials to provide additional data about the effectiveness of DEBs in treating atherosclerosis in the coronaries, the SFA, fempop and BTK.
As a stand-alone device the DEB has the potential to become the fourth successful and sustainable platform in the history of coronary and peripheral vascular intervention. Further clinical investigation will certainly clarify the level of future utilisation in each vascular bed, but in any case, DEBs may be here to stay.