Cardiovascular Medical Device Series: Introduction and Technical Trends in the Cardiac Rhythm Management Industry
Author: Emeli (Li) Zhang
Finished by April, 2016
Sudden cardiac death (SCD) is one of the most leading causes of natural death, causing more than 7 million deaths worldwide every year . It was estimated by the American Heart Association that SCD occurs in more than 400,000 Americans annually . Most of SCDs are caused by cardiac arrhythmias, characterized by abnormal hearth rhythm. An arrhythmia can cause the heart rate to be too low below 60 beats per minute - called bradycardia or too fast above 100 beats per minute - called tachycardia. Cardiac rhythm management refers to a progress of providing therapeutic solutions to patients suffering from cardiac arrhythmias, and has advanced significantly in the last 60 years. Therapeutic solutions primarily comprise anti-arrhythmic drugs, cardiac implantable electronic devices (CIEDs) and ablation procedures. From the perspective of device-guided therapy, the cardiac rhythm management market/industry can be categorized as pacemakers, defibrillators and cardiac resynchronization therapy (CRT) devices.
A pacemaker is an electronic device capable of sensing the intrinsic hearth rhythm and is used to maintain cardiac contraction when the heart’s natural pacemaker (e.g. the sinoatrial node) is dysfunctional or the electrical conduction pathways are somewhat blocked, causing a slow heart rate.
Pacemakers were developed in the 1950s, and the first fully implantable pacemaker was implanted in humans by Dr. Ake Senning in Sweden in October,1958 using thoracotomy for epicardial electrode implantation . Transvenous leads were then developed and the first implanted pacemaker with transvenous leads was used by Parsonnet in US in early 1960s . Early generations of pacemakers have very limited functionality and short life-time. Rapid advances have driven pacemaker to evolve from single-chamber pacing with fixed rate to multi-chamber with responsive-rate that can detect changes in the patient’s physical activities and automatically program the rate to meet the physical needs. Lead implantation has moved from thoracotomy placement to minimally invasive transvenous placement. Three approaches to permanent cardiac pacing are currently used to treat different cardiac conditions, including single-chamber pacemaker with one lead implanted in right atrium or right ventricle, dual-chamber pacemaker with two leads implemented, one in right atrium and the other in right ventricle, and bi-ventricular pacing for CRT therapy with another epicardial lead placed to the coronary sinus site in addition to right heart pacing leads. Fig. 1 provides a diagram showing the working mechanism of an implantable pacemaker (courtesy to American Heart Association).
Technical developments primarily advances in battery longevity, lead technology and miniaturization, leading exponential increases in pacemaker’s functionality . In the global pacemaker industry, three key vendors progressively drive technology innovations such as Medtronic (Minneapolis, MN), St. Jude Medical (St. Paul, MN) and Boston Scientific, competing fiercely for the 6 billion pacemaker market. Among three, Medtronic alone holds more than 50% market share steadily and St. Jude is secondary. Fig. 2 and 3 show the technological evolutions of pacemakers in Medtronic and St. Jude Medical, respectively.
Despite revolutionized advances in the past decades, various limitations still exist shown in table 1 , applicable to all CIEDs. The most prominent two long-term issues with implantable pacemakers are infection and lead failure caused by lead dislocation and fracture. It was estimated that 65,000 lead failures occur annually in more then 4 million CIED implantations worldwide . A lead extraction procedure is determined by the physician when lead fracture, large amounts of scar tissue identified at the lead tip, or infection at the lead site occurs . Despite high success rate, this procedure is still risky and might have complications such as bleeding and discomfort. In 2014, it was reported by European Heart Rhythm Association that there are 15-60 lead extraction procedures annually occurs in 1000 CIED implantations per million residents . Among three components for a traditional implantable pacemaker (lead, pulse generator and battery), the tranvenous lead is the weakest point. In 1970, Dr. Spickler and his colleagues reported a completely self-contained pacemaker, i.e. leadless pacemaker, implanted through a transvenous sheath  (see the device in Fig. 4). The concept of a leadless pacemaker has been developed for decades. The limitations of totally implantable intracardiac or leadless pacemakers are related to stability of pacing and sensing, low energy communication system with a remote device, replacement feasibility and the device size .
Since 2014, two leadless pacemaker products including Nanostim (St. Jude Medical) and Micra (Medtronic) have been gone through clinical studies. The Nanostim pacemaker, known as the world’s first pacemaker, was originally developed by Sunnyvale, California-based Nanostim and was bought by St. Jude for $123.5 million in 2013. Medtronic developed Micra, the world smallest pacemaker, in house and the Micra Transcatheter Pacing System (TPS) comprises a delivery system, an introducer and the pacemaker device. The Nanostim clinical trail enrolled 667 patients at 56 enters across US, Canada and Australia, and achieved successfully implant rate 95.8% with a major complication rate 6.7% . In comparison, the Micra leadless pacemaker clinical trial enrolled 725 patients at 56 enters in 19 countries cross 5 continents and achieved high successful implant rate 99.2% with a low major complication rate 4% . The Micra study reported no device detachment, while device detachment occurred in 1.1% of patients in the Nanostim study . Both clinical trials have follow-up data in 300 patients. With the current available statistical data, Micra is doing slightly better than Nanostim in terms of successful implant rate and major complication rate. Nanostim got CE Mark in Oct. 2013 and Micra was awarded CE Mark in Apr. 2015. Both Medtronic and St. Jude presented to the FDA’s Circulatory System Devices Panel on Feb. 2016 for overviewing the clinical experiences and discussing the post approval study design. On April 6, 2016, FDA approved the Medtronic Micra TPS to treat heart rhythm disorders for US patients . Fig. 5 shows the Medtronic Micra TPS implantable device. Medtronic Micra was the first FDA approved leadless pacemaker with miniaturized pacing technology! The Micra TPS is just one-tenth the size of traditional pacemaker and is the first being approved for being compatible with both 1.5 and 3T MRI systems. The leadless pacing and sensing technology is superior over the traditional pacing technology and is expected to eliminate all complications caused by transveneous leads. Leadless pacemakers just kicked off its era, and there are several questions that remain to be answered: “the reliability and consistent performance can last in the long term? the rates of device detachment over time are unknown? is the device retrievable readily and allow easy replacement when necessary? will the battery life time is really more than 10 years as claimed?”. In addition, the current leadless pacemaker only allows a single-chamber rate-responsive pacing and is applied to the right ventricle pacing. There are other clinical conditions that require dual-chamber pacing and biventricular pacing for CRT. Therefore, there are other possibilities in technology innovations pointing toward a bright future for leadless pacing.
Implantable Cardioverter Defibrillators
A defibrillator is a device to treat for life-threatening cardiac arrhythmias by delivering an electrical current to the heart in order to terminate the arrhythmias and then reestablish the normal heart rhythm. Defibrillators can be external or implanted (implanted cardioverter defibrillator — ICD). Manual and automated external defibrillators are used by the healthcare professionals to deliver proper electrical therapy to people who undergo life-threatening cardiac events such as ventricular tachycardia (VT), atrial/ventricular fibrillations (AF/VF). Manual external defibrillators can generally only be found in hospitals and on some ambulances, while automated external defibrillators (AED) can also be in public access . It was reported that survival rates for patients with ventricular fibrillation treated by AEDs are in the range of 0-31%, while the survival rates with basic cardiopulmonary resuscitation solely is in the range of 0-6%.
This report will be focused on technical advances and trends in implantable cardioverter defibrillator. An ICD is a device placed under the skin with wired leads connected to the heart. It keeps track of the heart rate and delivers an electrical shock to restore the normal rhythm when detects an abnormally fast rhythm. The ICD therapy is used to treat patients who have sustained VT or frequently recurring VT for preventing sudden cardiac death or cardiac arrest. The first ICD implantation in humans occurred in 1980 and approved by FDA in 1985. A brief introduction of the evolution of ICD is available in MedScape .
Currently, lead implantation can include one lead in the right ventricle (single chamber ICD), two leads with one in the right atrium and the other in the right ventricle (dual chamber ICD) or three leads with one, in the right atrium, one in the right ventricle and the last one on the epicardial surface of the left ventricle (biventricular ICD). Technical advances in miniaturization, longer battery and less invasive lead implantation have made ICDs safer to patients in the long term. In the global ICD market, four companies include Medtronic, Boston Scientific, St. Jude Medical and Biotronik hold more than 90% of the market shares. Medtronic’s market shares in ICD accounts for nearly 50%.
Introduction of quadripolar leads for ICD has been one of the significant innovations. The quadripolar leads with 4 electrodes facilitating more programable pacing options can overcome issues with lead placement, particularly benefits the patients not responsive to other pacing technologies in CRT defibrillator (CRT-D) therapy. It was reported in MORE-CRT trial that there is a smaller intra- and post-operative LV lead complication rate with quadripolar leads than bipolar leads . The first FDA approval to the quadripolar pacing technology was issued to St. Jude Medical in Jan. 2012 on its Unify Quadra CRP-D and Quartet left ventricular quadripolar pacing lead . In Apr. 2014, Boston Scientific received the FDA approval of its X4 line of quadripolar CRT-Ds, which "offers 70 percent more pacing options to address high capture thresholds and phrenic nerve stimulation effectively" with the battery life time up to 6 years . Then Medtronic received the FDA approval for its Attain Performa Model 4298 quadripolar lead and the Viva Quad XT and Viva Quad S CRT-Ds with 16 pacing configurations and shorter spacing between two centre electrodes allowing physicians to treat patients with different anatomies . And in Dec. 2014 Medtronic commercially launched two additional LV quadripolar leads that can be paired with S-shape and Straight leads for accommodating patients’ varying vessel sizes and curvatures to enhance successful lead placement . Fig. 6. shows the Medtronic Viva Quad XT CRT-D system with the Attain Performa Quadripolar lead. In Feb. 2016, Boston Scientific receive the FDA approval fro its ACUITY X4 Quadripolar LV leads, allowing the company to offer the full X4 CRT system, both the device and the leads to the US market .
Subcutaneous ICD (S-ICD) was developed for patients where implantation of transvenous leads or epicardial patches is not practical or at high risk of morbidity and mortality. Fig. 7 shows the comparison between a SCD and a transvenous ICD. Transvenous leads are a major cause for inappropriate shock, short- and long-term complications and ICD failure. S-ICD was designed to address these issues. Unless the transvenous ICDs, there is no need for placement of leads inside heart for S-ICD and the whole device including the pulse generator and electrodes is placed just below the skin. Boston Scientific got the FDA approval of the first S-ICD in Oct. 2012 . Sales of the S-ICD are more than $100 million per quarter, and Boston Scientific is putting efforts in developing leadless pacemaker with paring with its ICD to treat a wide range of patients in heart failure.
There are strong demands from patients for getting MRI scans for diagnosis of clinical conditions after being implanted with ICDs. In Sep. 2015, FDA approved the first MRI-safe ICD, the Evera MRI SureScan ICD system from Medtronic. This product has been approved for MRI scans at any part of the body. This system is MR-conditional, that is said, the ICD has to be paired with compatible Sprint Quattro Secure MRI SureScan DF4 leads . The system along with its MR comparable leads got CE Mark in Apr. 2014. Boston Scientific also got CE Mark for MRI compatible labeling for ICD and CRT-D systems .
In additions to quadripolar leads, S-ICD and MRI safe ICDs, advances in improving battery and reducing the incidence of inappropriate shocks also actively carry on, facilitating better healthcare for patients with the ICD therapy.
Cardiac Resynchronization Therapy
CRT, also referred to biventricular pacing, is designed to resynchronize contractions of the left and right ventricles by simultaneous pacing the ventricles when detects irregular rhythms and also can keep them in sync with the atriums. Traditional pacemakers are designed to treat bradycardia (i.e. slow heart rhythms). Dual-chamber pacemakers are used to keep the atrium and ventricle working together using one lead implanted in right atrium and the other in right ventricle. Biventricular pacemakers (CRT devices) usually have a third lead implanted in the coronary artery sinus site via a vain other than dual-chamber pacemakers and sometimes only use two leads in the ventricles. There are two types of CRT devices including a CRT pacemaker (CRT-P) and a CRT-D. all CRT devices have pacing functions, while CRT-D also have defibrillation function like a defibrillator. Four vendors including Medtronic, Boston Scientific, St. Jude Medical and Biotronik drive the CRT device global market. The recent revolutionized innovation for CRT is the introduction of quadripolar pacing technology as discussed in the Implantable Cardioverter Defibrillator section.
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