1. substernal icd 2. vldl 3. polypill tips 3 trial

1. PRESENTER – DR SIVANAND PATEL
DM CARDIOLOGY (MAMC & GB PANT hospital )

2. 1. First-in-Human Chronic Implant Experience of the Substernal Extravascular
Implantable Cardioverter-Defibrillator
2. VLDL Cholesterol Accounts for One-Half of the Risk of Myocardial
Infarction Associated With apoB-Containing Lipoproteins
3. Polypill with or without Aspirin in Persons without Cardiovascular Disease

4.  ICDs -> cornerstone in the management of patients at risk for sudden cardiac death
 Transvenous lead ->
◦ Concerns related to defibrillation lead failure( achilles heel of ICD )
◦ Vascular obstruction
◦ Device-related systemic infections
◦ Significant associated morbidity and mortality

5.  SQ ICD -> allows the delivery of defibrillation and cardioversion has limitations:
◦ No antitachycardia pacing (ATP) pacing support aside from post-shock pacing
◦ high-energy system -> large and often uncomfortable device with less longevity .
 The EV defibrillator uses a novel substernal lead placement to address these
limitations.
Boersma L, Barr C, Knops R, et al. Implant and midterm outcomes of the subcutaneous implantable
cardioverter-defibrillator registry: the EFFORTLESS study. J Am Coll Cardiol 2017;70:830–41.

6.  EV ICD pilot study - prospective, nonrandomized , chronic, first-in-human study
 4 centers in Australia and New Zealand

7.  The EV ICD ->use the substernal space.
 size same as that of a transvenous ICD (33 cm3) / delivering up to 40 J .
 2 pace/sense electrodes and 2 defibrillation coil segments

8.  3 cm incision -> between the xiphoid and left costal margin to access the substernal space .
 Blunt dissection was performed to the rectus fascia on the posterior border of the left xiphoid
rib junction and then advanced through the diaphragmatic attachments to enter the anterior
mediastinum.
 Tunneling tool with peelaway sheath was introduced into the substernal space and advanced
under lateral fluoroscopy to ensure that the tip of the tunneling tool was adjacent to the
posterior face of the sternum to avoid cardiac injury.
 Tunneling path was created to the upper heart silhouette using AP fluoroscopy .

9.  Defibrillation lead was inserted into the substernal space via the peel-away
introducer sheath once the tunneling tool had been removed.
 Acute sensing measurements were collected with the expectation of R-wave
amplitudes $1 mV.
 Lead was then secured to the rectus sheath .
 Proximal portion of the lead was then tunneled to an SQ device pocket on the left
side of the chest .
 Device placed over the serratus muscle and was sutured within the pocket.
 Electrical parameters, including sensing, impedance, and pacing in multiple
vectors, were measured through the device by telemetry.

12. EV ICD offer opportunity for :
Lower DFT , smaller device size & greater longevity
pacing (asystole pacing support , ATP ) in a single device

13.  Inclusion criteria
◦ Class I or IIa indication on the basis of current clinical practice guidelines
Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and
 Exclusion criteria
◦ Indication for bradycardia pacing or CRT .
◦ Existing implanted device or prior cardiac implanted device .
◦ Any condition that would compromise access to the anterior mediastinum, including
previous sternotomy, prior chest radiotherapy,
◦ Any condition that would prevent defibrillation testing
 LV thrombus , severe AS , severe COPD
 LVEF <20%
◦ Any abnormality that would increase implantation risk
 severe obesity , marked RV dilation
 anticoagulation that could not be interrupted , active infection or renal dialysis.

14.  Primary efficacy endpoint
◦ Was defibrillation testing success at implantation.
 Implantation required termination of VF with
◦ either a single 20-J shock or on 2 consecutive episodes with a 30-J shock.
 If the patient was successfully defibrillated at 20 J, defibrillation efficacy was assessed at 15J.
 Primary safety endpoint
◦ any complication related to the EV ICD system or procedure that resulted in death, system
revision, hospitalization, prolongation of a hospitalization, or permanent loss of
defibrillation function due to device dysfunction.

17. 17 of 19 patients defibrillated with <30 j
Median energy for defibrillation : 15 j

18.  Acute pacing successful in 19 of 20 patients (95%) at <= 10 volts
◦ Patient with no capture only tested to 8 volts
◦ threshold at implant : 5.1 +-1.9 volts
 Partients generally aware of pacing stimulus at threshold

21.  No major complications -> during procedures.
 One patient experienced an inappropriate shock 78 days post-implantation because of P-
wave oversensing that occurred when the lead tip deflected toward the right atrial
appendage.
 Explanted at 85 days post-implantation without complication using only simple traction
for lead removal; the patient then received a SQ defibrillator.
 90-day rate of freedom from systemic or procedural major complication was 94.1% .

22.  2 patient -> inspiratory discomfort post-operatively
 3 minor wound issues -> resolved without sequelae.
 Beyond 90 days, 1 patient with ARVD underwent investigator initiated elective chronic
defibrillation testing at 3 months .
 At implantation, this patient passed testing by defibrillating in 2 consecutive episodes at 30 J;
however, at elective retesting, there was successful defibrillation at 40 J, but not 30 J .
 The system was removed at 114 days post-implantation without complication using simple
traction for lead removal and replaced by an SQ defibrillator .

23.  EV ICD first-in-human chronic study demonstrates the ability to position a
substernal defibrillation lead and to achieve high effectiveness for acute
defibrillation, pacing, and sensing.
 EV ICD - proximity to the heart results in a lower energy requirement for cardiac
defibrillation and provides potential for ATP and asystole support pacing features
not available in the SQ ICD, while offering a truly EV system placement .

24.  Reasons for explantation
 limited inducibility and poor sensing in 1 patient
 1 failed implantation due to mediastinal fibrosis
 failed defibrillation testing in 2 patients
 2 elective explantations due to lead dislodgement
 1 failed repeat defibrillation testing.

25. Only short-term follow-up data in a small cohort of predominantly male patients from a
single geographic region are available .

26.  First-in-human evaluation of the EV ICD system demonstrated the feasibility of substernal
lead placement, defibrillation, and pacing with a chronically implanted system.
 No acute major complications .
 Indiuced VF detected at 0.3 mV in all patients
 Pacing was effective in 95% of patients
 Clinical VT was succesfully treated in one patient .
 15 Patient continue to be followed chronically
 Learning from pilot study will be leveraged for system enhancement and future pivotal study .

27.  Although long-term data are required for the novel extravascular ICD system, a substernal
lead strategy may overcome the substantial morbidity and mortality associated with the
introduction and long-term position of transvenous leads in the heart.
 Extravascular ICD platform provide bradycardia and ATP options, as well as defibrillate
the heart with energy levels similar to current TV ICD platforms.

30.  Elevated triglyceride (TG) rich remnants or very low-density lipoproteins (VLDLs) are
associated with increased risk of atherosclerotic cardiovascular disease (CVD) .
 RCTs using TG lowering therapies mainly in individuals without elevated TGs yielded
conflicting results on cardiovascular endpoints .
 Unclear which fraction of risk is explained by respectively cholesterol and TGs in
VLDL.
Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease.
Lancet 2014;384: 626–35.

31.  VLDL cholesterol and TGs each explain part of the MI risk from apoB-containing
lipoproteins

32.  STUDY POPULATION.
 Copenhagen General Population Study is an ongoing study initiated in 2003
 Prospective study of 25,480 individuals
 Inclusion criteria –
◦ Free of lipid-lowering therapy and myocardial infarction at study entry
 Exclusion criteria –
◦ With MI before baseline and individuals receiving lipid-lowering therapy.

33.  LIPOPROTEINS.
 Cholesterol and TG content of VLDL, IDL, and LDL - measured ( NMR spectroscopy )
 Nonfasting blood samples were used.

34.  RISK OF MYOCARDIAL INFARCTION. hazard ratio
 2.07 for VLDL cholesterol
 1.19 for VLDL triglycerides
 5.38 for IDL cholesterol
 1.86 for LDL cholesterol.
 2.21 for plasma apoB,.

36.  During a median 11 years of follow-up, 1,816 were diagnosed with myocardial infarction.
 Risk factors for myocardial infarction entered by importance as
◦ VLDL cholesterol >systolic blood pressure >smoking > IDL + LDL cholesterol
◦ VLDL cholesterol explained 50% and IDL + LDL cholesterol 29% of the risk of
myocardial infarction from apoB-containing lipoproteins, whereas VLDL triglycerides
did not explain risk.

37.  The study found
◦ VLDL explained one-half of the risk of MI (elevated levels of apoB containing lipoproteins )
◦ VLDL TGs did not materially add to the explanation of risk .
 Here document for the first time by head-to-head comparison that the cholesterol and
not the TG content of TG-rich lipoproteins explains a large fraction of the increased risk
of MI from elevated concentrations of apo B containing lipoproteins.
Ference BA, Kastelein JJP, Ray KK, et al. Association of triglyceride-lowering LPL variants and LDL-C-lowering LDLR
variants with risk of coronary heart disease. JAMA 019;321:364–73.

42.  Large number of individuals recruited from the general population
 Median follow-up - 11 years without losing track of any individual
 A large number of MI during follow-up

43.  Observational design
 Included solely white individuals .

44.  VLDL cholesterol explained one-half of the MI risk from elevated apoB-containing
lipoproteins, whereas VLDL TGs did not explain risk.

46. Cholesterol with in TG-rich lipoproteins -> atherogenic agent .
TG inside this family of particles are less toxic .
This study , directly measured VLDL cholesterol emerged as the most important MI risk
factor, ahead of SBP , smoking, and IDL / LDL cholesterol.
What do these studies mean for the clinical cardiologist?
 Although VLDL cholesterol is for prediction, LDL cholesterol retains predictive power.
 NMR methodology, promising, and it needs to be further field tested and validated.
 Addition to lipid profile, newer analytes such as remnant cholesterol as well as
lipoprotein(a) and apo B are reported to improve prognostication and help guide
preventive treatments (18).

49.  Elevated blood pressure (BP )and an elevated level of low-density lipoprotein
(LDL) cholesterol -> modifiable risk factors for cardiovascular disease(CVD ) .
 “polypills,” -> combine lipid-lowering and BP –lowering medications .
 Aspirin role as part of a polypill for the primary prevention of CVD is unclear.
Zheng SL, Roddick AJ. Association of aspirin use for primary prevention with cardiovascular events and
bleeding events; a systematic review and metaanalysis. JAMA 2019; 321: 277-87

53. Whether treatment with a polypill consisting of a statin and multiple blood-
pressure–lowering drugs, aspirin alone, or their combination would reduce the
incidence of cardiovascular events among persons without cardiovascular
disease.

54.  The goal of the trial was to assess the safety and efficacy of a once-daily polypill and aspirin
among patients with intermediate cardiovascular (CV) risk.
 TIPS-3 double-blind, randomized, placebo controlled trial
 5713 participants , 86 centers in nine countries.
 July 30, 2012, and August 12, 2017 ; Follow up 4.6 years
 Comparisions
◦ Polypill ( 40 mg of simvastatin +100 mg of atenolol + 25 mg of hydrochlorothiazide + 10
mg of ramipril vs placebo ) on the incidence of CV outcomes.
◦ Enteric-coated aspirin at a dose of 75 mg per day, as compared with placebo, on the
incidence of CV outcomes (primary outcome) and the composite of CV outcomes and
cancer (secondary outcome).
◦ Polypill plus aspirin as compared vs double placebo.

58. Inclusion criteria:
 Men aged ≥50 years and women aged ≥55 years with an INTERHEART risk score ≥ 10
 men and women aged ≥65 years with an INTERHEART risk score of ≥5.
Exclusion criteria:.
 Clear clinical indication, contraindication, preference for or intolerance to statin, beta
blocker (eg, bradycardia), ACE inhibitor, diuretic, aspirin or clopidogrel in the judgment
of the physician
 Known vascular disease. (eg, Stroke, TIA, Angina, MI, ACS, PVD including claudication
and amputation).
 Mean systolic BP below 120 mm Hg at run-in.
 abnormal liver function, i.e. ALT or AST >3 × ULN.
 Severe renal impairment (serum creatinine >264 μmol/L).
 History of malignancy within the previous 5 years.

59.  Procedures
 Run-in phase (4 weeks )-> low dose polypill (half doses of BP–lowering medications
plus 40 mg of simvastatin) and low-dose aspirin (75 mg) daily.
 who had at least 80% adherence to these medication regimens, who did not have adverse
events, and who agreed to undergo randomization were assigned to receive a full-dose
polypill or matching placebo, aspirin or matching placebo .
 A low-dose polypill (or matching placebo) or a polypill with full doses of each
component except ramipril (or matching placebo) were available for participants who
had dizziness, hypotension, or cough.

60.  PRIMARY OUTCOME
◦ For the polypill-alone and polypill-plus-aspirin comparisons
 death from cardiovascular causes,
 myocardial infarction,
 stroke,
 resuscitated cardiac arrest
 heart failure
 revascularization.
◦ For the aspirin comparison
 death from cardiovascular causes
 Myocardial infarction, or stroke.

61.  LDL was lower by 19 mg % and SBP lower by 5.8 mm Hg with the polypill and with
combination therapy than with placebo.
 The primary outcome for the polypill comparison occurred in 126 participants (4.4%) in
the polypill group and in 157 (5.5%) in the placebo group . (hazard ratio, 0.79)
 The primary outcome for the aspirin comparison occurred in 116 participants (4.1%) in
the aspirin group and in 134 (4.7%) in the placebo group (hazard ratio, 0.86; 95% CI,
0.67 to 1.10). (hazard ratio, 0.86 ) .
 The primary outcome for the polypill + aspirin comparison occurred in 59 participants
(4.1%) in the combined-treatment group and in 83 (5.8%) in the double placebo group .
(hazard ratio, 0.69 ) .
 The incidence of hypotension or dizziness was higher in groups that received the
polypill than in their respective placebo groups.

62. Effects of the Polypill, as Compared with Placebo, on Systolic Blood Pressure, I bars indicate
95% confidence intervals (CIs).

63. Effects of the Polypill, as Compared with Placebo, on Heart Rate I bars indicate 95% confidence
intervals (CIs).

64. Effects of the Polypill, as Compared with Placebo, on the Low-Density Lipoprotein (LDL)
Cholesterol Level. I bars indicate 95% confidence intervals (CIs).

65. Effects of the Polypill, as Compared with Placebo, on Clinical Outcomes.
Panel A shows the cumulative incidence of a first composite-primary-outcome event (death from
cardiovascular causes, myocardial infarction, stroke, heart failure, resuscitated cardiac arrest, or
arterial revascularization) for the comparison of the polypill with placebo.

66. Effects of the Polypill, as Compared with Placebo, on Clinical Outcomes.
Panel B -> cumulative incidence of first and recurrent events of the primary composite
outcome. Insets show the same data on an enlarged y axis

68.  Effects of the Aspirin, as Compared with Placebo, on Clinical Outcomes. Panel A shows the
cumulative incidence of a first composite-primary-outcome event (death from cardiovascular
causes, myocardial infarction, or stroke) for the comparison of aspirin with placebo.

69. Effects of the Aspirin, as Compared with Placebo, on Clinical Outcomes. Panel B shows the
cumulative incidence of the first event of cancer (component of the secondary outcome; a
prespecified outcome). Insets show the same data on an enlarged y axis.

71. Effects of the Polypill plus Aspirin, as Compared with Double Placebo, on Clinical Outcomes.
Panel A shows the cumulative incidence of a first composite-primary-outcome event (death from
cardiovascular causes, myocardial infarction, stroke, heart failure, resuscitated cardiac arrest, or arterial
revascularization) for the comparison of combination therapy with a polypill plus aspirin with placebo.

72. Effects of the Polypill plus Aspirin, as Compared with Double Placebo, on Clinical Outcomes.
Panel B shows the cumulative incidence of first and recurrent events of the primary composite outcome.
Insets show the same data on an enlarged y axis.

74.  Trial discontinuation - medications vs placebo polypill-plus-aspirin vs double-placebo
group
 Similar
 5 vs 7 muscle symptoms
 3 and 1 because of GI bleeding
 3 and 3 because of dyspepsia
 19 and 22 because of gastritis
 3 and 3 because of peptic ulcer
 9 vs 12 Major bleeding
 higher incidence (significant )
 dizziness or hypotension (45 vs. 22 participants).
 hypotension, dizziness, and cough

75.  TIPS-3, polypill + aspirin administered ( mean of 4.6 years ) primary-
prevention population at intermediate risk led to a 31% lower relative risk of
cardiovascular events .
 Reduction in LDL with the polypill was half the value that had anticipated on
the basis of previous trials of simvastatin at a dose of 40 mg per day, the TIPS-1
and TIPS-2 pilot studies .

76.  Combination treatment with a polypill plus aspirin led to a lower CV events than placebo
(participants without established cardiovascular disease who were at intermediate CV risk )
 Once-daily polypill was superior to placebo in reducing systolic BP, LDL-C, and nonfatal
CV events (at 5 years) among intermediate CV risk patients (Southeast Asia )
 Low-dose aspirin -> lower stroke risk.
 low-dose aspirin + polypill -> greater reduction in nonfatal CV events .

77.  Out of 7534 run-in phase did not undergo randomization
◦ 715 (9.5%) because of side effects & 560 participants (7.4%) less than 80%
adherence
 TIPS-3 -> may underestimate the number of persons who would stop treatment for
side effects or poor adherence if a polypill including aspirin were used in eligible
general population.

78.  Polypill -> Improve adherence .
 In the polypill–placebo analysis, primary cardiovascular outcome (CV death, MI , stroke,
heart failure, or revascularization) was nonsignificantly less frequent in polypill recipients
than placebo recipients (4.4% and 5.5%).
 In the aspirin–placebo analysis, the primary outcome (CV death, MI, or stroke) was
nonsignificantly less frequent in aspirin recipients than placebo recipients (4.1% and 4.7%).
 In the combined analysis, the primary outcome was significantly less frequent in the
polypill-plus-aspirin group than the double-placebo group (4.1% vs.5.8%; hazard ratio, .69).
 The polypill-plus-aspirin group had more hypotension and cough, but not bleeding, than
the double-placebo group.

79.  Polypill-plus-aspirin strategy lowers CV events in a primary-prevention population.
 Effect on western populations remains unknown.
 Instead of atenolol ; other medications might have yielded better results.
 24% of screened participants failed the run-in phase, primarily due to side effects.
 Adherence remained suboptimal; at study's end, discontinuation of the polypill was
42% and discontinuation of aspirin was 40%.

80.  Inclusion criteria
◦ Without previous cardiovascular disease
◦ Aged between 45 years and 80 years
◦ With one risk factor (type 2 diabetes; blood pressure >140 mm hg systolic /90 mm hg
diastolic, but <160/100 mm hg;
◦ Smoker within past 5 years; increased waist to hip ratio [>0・85 for women and >0・90
for men]; or abnormal lipids [LDL cholesterol >3mmol/L or HDL cholesterol
<1mmol/L]).
 Exclusion criteria –
◦ Receiving one of the study drugs
◦ Taking two or more antihypertensive drugs
◦ Serum LDL cholesterol greater than 4・5 mmol/L,
◦ Creatinine greater than 177 μmol/L (2・0 mg/dl) or k > 5・5 mmol/L,
◦ Abnormal liver function

81. Inclusion criteria
 Were 40 years or older with a seated BP≥130/80 mm Hg on 2 consecutive occasions (or
BP≥120/80 mm Hg on antihypertensive drugs)
 Vascular disease or high-risk diabetes mellitus (HbA1c<7.5%, with microalbuminuria or
BP>140/90 mm Hg)
Exclusion criteria
 Known intolerance to, or a clear indication for any of the study drugs
 Planned or recent coronary intervention or surgery
 Renal dysfunction (serum creatinine>2 mg/dL [176.8 μmol/L]
 Serum K>5.0 mEq/L
 Estimated glomerular filtration rate<45 ml/min/1.73 m2)
 Inability to attend follow-up visits