land mark trials 2015

Land mark trials in 2015

Dr K. V. Siva krishna

Topic outline• Recent trials on • Hypertension • Heart failure• ACS• Lipids• PAH• Miscellaneous

SPRINT trial

• The SPRINT trial • A Randomized Trial of Intensive versus

Standard Blood-Pressure Control.

• Among persons 50 years of age or older, isolated systolic hypertension is the most common form of hypertension, and systolic blood pressure becomes more important than diastolic blood pressure as an independent risk predictor for coronary events, stroke, heart failure, and end-stage renal disease.

• Clinical trials have shown that treatment of hypertension reduces the risk of cardiovascular disease outcomes, including incident stroke (by 35 to 40%), myocardial infarction (by 15 to 25%),and heart failure (by up to 64%).

• The target for systolic blood-pressure lowering is uncertain.

• The current trial Systolic Blood Pressure Intervention Trial (SPRINT), compared the benefit of treatment of systolic blood pressure to a target of less than 120 mm Hg with treatment to a target of less than 140 mm Hg.

Eligibility, Randomization, and Follow-up.

The SPRINT Research Group. N Engl J Med 2015;373:2103-2116

STUDY DESIGN

• PRIMARY OUTCOMES:• COMPOSITE of

myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure, or death from cardiovascular causes.

• Secondary outcomes• Included the individual

components of the primary composite outcome, death from any cause, and the composite of the primary outcome or death from any cause

• Renal outcome• With chronic kidney disease

decrease in the eGFR of 50% or more or the development of ESRD requiring long-term dialysis or kidney transplantation.

• decrease in the eGFR of 30% or more to a value of less than 60 ml per minute per 1.73 m2

Characteristic Intensive Treatment(N = 4678)

Standard Treatment(N = 4683

Age ≥75 yr 1317 (28.2) 1319 (28.2)

Chronic kidney disease‡ 1330 (28.4) 1316 (28.1)

Cardiovascular disease 940 (20.1) 937 (20.0)

Female sex — no. (%) 1684 (36.0) 1648 (35.2)Systolic bp 139.7±15.8 139.7±15.4

Diastolic 78.2±11.9 78.0±12.0Statin use — no./total no. (%)

1978/4645 (42.6) 2076/4640 (44.7)

Aspirin use — no./total no. (%)

2406/4661 (51.6) 2350/4666 (50.4)

Criterion for increased cardiovascular risk — no.

Baseline Characteristics of the Study Participants.

Systolic Blood Pressure in the Two Treatment Groups over the Course of the Trial.


Primary Outcome and Death from Any Cause.


245

314

Total deaths 365(155 Vs 210 ) p=0.003.

155

210

P=<0.0001

Forest Plot of Primary Outcome According to Subgroups.


Primary and Secondary Outcomes and Renal Outcomes.


Serious Adverse Events, Conditions of Interest, and Monitored Clinical Events.


Conclusions• Conclusion: • Among patients at high risk for cardiovascular

events but without diabetes, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group.

IMPROVE IT Trial

Study Overview• Ezetimibe targets the Niemann–Pick C1–like 1 (NPC1L1) protein, thereby reducing absorption of cholesterol from the intestine.

• When added to statins, ezetimibe reduces LDL cholesterol levels by an additional 23 to 24%, on average.

• The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) evaluated the effect of ezetimibe combined with simvastatin, as compared with that of simvastatin alone, in stable patients who had had an acute coronary syndrome and whose LDL cholesterol values were within guideline recommendations.

• In this trial, patients with an acute coronary syndrome within the previous 10 days were randomly assigned to simvastatin plus either ezetimibe or placebo

• Primary end point: composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke.

• The median follow-up was 6 years

STUDY PROTOCOL

Baseline Characteristics.

Cannon CP et al. N Engl J Med 2015;372:2387-2397

Kaplan–Meier Curves for the Primary Efficacy End Point.


Plot of the IMPROVE-IT Trial Data and Statin Trials for Change in Low-Density Lipoprotein (LDL) Cholesterol versus Clinical Benefit.


Primary, Secondary, and Individual End Points.


Prespecified Safety End Points.


Conclusions• In conclusion, the addition of ezetimibe to statin therapy

in stable patients who had had an acute coronary syndrome and who had LDL cholesterol levels within guideline recommendations further lowered the risk of cardiovascular events.

• The event reduction was consistent with the predicted effects seen with statins, even in the range of low LDL cholesterol levels in this trial, and no offsetting adverse events or toxic effects were observed.

• When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes.

• Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit.

MATRIX trial

• Two of the most commonly used antithrombotic worldwide are unfractionated heparin, an indirect thrombin inhibitor, with or without the concomitant use of a glycoprotein IIb/IIIa inhibitor, and bivalirudin, a direct thrombin inhibitor, with a glycoprotein IIb/IIIa inhibitor added only for periprocedural ischemic complications.

Time-to-Event Curves through 30 Days

Stone GW et al. N Engl J Med 2008;358:2218-2230

HORIZONS AMI TRIAL

Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial

Figure 2

The Lancet 2014 384, 1849-1858DOI: (10.1016/S0140-6736(14)60924-7)

Compared with bivalirudin, heparin reduces the incidence of major adverse ischaemic events in the setting of PPCI, with no increase in bleeding complications. Systematic use of heparin rather than bivalirudin would reduce drug costs substantially

• MATRIX Antithrombin was a randomized comparison of bivalirudin and unfractionated heparin involving 7213 patients with ST segment elevation myocardial infarction (STEMI) or a non–ST-segment elevation acute coronary syndrome for whom PCI was planned

• MATRIX Treatment Duration was a randomized comparison of prolonged bivalirudin administration with a post-PCI infusion with short-term bivalirudin administration without a post-PCI infusion,

STUDY DESIGN• Total patients(7213)

Bivaluridin group(3610) Unfractionated heparin group(3603)

Post PCI infusion (1799)

No post PCI infusion (1811)

• Coprimary outcomes• Major adverse cardiovascular

events,: a composite of death from anyNcause, myocardial infarction, or stroke, up to 30 days, and

• net adverse clinical events,Bleeding Academic Research Consortium [BARC] type 3 or 5 or major adverse cardiovascular events, up to 30 days.

• Primary outcome (MATRIX Treatment Duration)

• composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events up to 30 days

• Secondary outcomes • Death from cardiovascular• causes, and stent thrombosis. • Bleeding was also assessed and

adjudicated on the basis of the Thrombolysis in Myocardial Infarction (TIMI) and

• Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO17) scales.

Characteristics of the Patients at Baseline.

Valgimigli M et al. N Engl J Med 2015;373:997-1009

Coprimary Composite Study Outcomes at 30 Days.


Primary Composite Outcome at 30 Days, According to Duration of Bivalirudin Infusion.


Clinical Presentation and Medications at Baseline.


Clinical Outcomes up to 30 Days.


Conclusions• In patients with an acute coronary syndrome,

the rates of major adverse cardiovascular events and net adverse clinical events were not significantly lower with bivalirudin than with unfractionated heparin.

• The rate of the composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events was not significantly lower with a post-PCI bivalirudin infusion than with no post-PCI infusion.

CONCLUSIONS• In conclusion, among patients with acute coronary

syndromes undergoing invasive treatment, neither the rate of major adverse cardiovascular events nor the rate of net adverse clinical events was significantly lower with bivalirudin than with unfractionated heparin and discretionary use of glycoprotein IIb/IIIa inhibitors.

• The post-PCI infusion of bivalirudin for at least 4 hours after the intervention did not result in a lower rate of the composite outcome of ischemic and bleeding events, including stent thrombosis, than the rate with no post-PCI infusion.

AMBITION trial

Background • Current therapies for pulmonary arterial hypertension

target abnormalities in one of three intracellular pathways with signaling dysfunction:

• The prostacyclin, nitric oxide, or endothelin pathway. However, no single class of drug is consistently effective in treating all patients, which suggests that no single pathway plays a dominant pathogenic role

• Data on the effect of initial combination therapy with ambrisentan and tadalafil on long-term outcomes in patients with pulmonary arterial hypertension are scarce.

Inclusion criteria• 18 and 75 years of age• Weight >40 kg• WHO Functional Class II or III i. mPAP of >25 mmHg ii. PVR >240 dynes.sec/cm5 iii. PCWP/LVEDP of ≤15 mmHg

Exclusion criteria• Received previous PAH therapy

(PDE5i, ERA, chronic prostanoid*) within 4 weeks prior to the Screening Visit

• Pregnant females• Inotropes with in past 2 weeks

before enrollment• Known hypersensitivity to drugs

Patient selection

Follow-up (at weeks 4, 8, 16, and 24 andevery 12 weeks thereafter)

Ambrsentan+Tadalafil

Ambrsentan ALONE

End of the study

Study design

Tadalafil alone

Randomisation done in 2:1:1 ratio 0

253 patients

126 patients

121 patients

Mean follow up 610 days

Total of 500 patients

End points• Components of the

Primary End Point• Death from any cause

• Hospitalization for

worsening pulmonary arterial hypertension

• Disease progression • Unsatisfactory long-term

clinical response

• Secondary end points

• Change from baseline to week 24 in N-terminal

• Pro–brain natriuretic peptide (NT-proBNP) level

• 6-minute walk distance, WHO functional class, and Borg dyspnea index

Characteristic Combination-Therapy Group(N = 253

Pooled-MonotherapyGroup(N = 247

Ambrisentan-MonotherapyGroup(N = 126

Tadalafil-MonotherapyGroup(N = 121

Age 54.5±14.3 54.2±14.9

53.9±14.7 54.5±15.2

Female sex — no. (%) 188 (74) 200 (81) 100 (79) 100 (83)

Hypertension 104 (41) 95 (38) 52 (41) 43 (36)

Diabetes 19 (8) 30 (12) 13 (10) 17 (14)

Coronary artery disease

16 (6) 4 (2) 2 (2) 2 (2)

Idiopathic 127 (50) 138 (56) 72 (57) 66 (55)

Associated with connective-tissue disease

103 (41) 84 (34) 44 (35) 40 (33)

Classification of pulmonary arterial hypertension— no. (%)

Demographic and base line characteristics

Disease Severity at Baseline.

Galiè N et al. N Engl J Med 2015;373:834-844

Results • A total of 123 participants had a primary

endpoint event up to the time of the final-assessment visit, including 46 (18%) in the combination- therapy group and 77 (31%) in the pooled monotherapy group (43 [34%] in the ambrisentan- monotherapy group and 34 in the tadalafil-monotherapy group.

Primary and Secondary Efficacy End Points.


Kaplan–Meier Curves for the Probability of a First Adjudicated Primary End-Point Event.


Safety• Peripheral edema, headache, nasal congestion

and anemia were more common in the combination- therapy group than in either monotherapy group, dizziness was more common in the combination-therapy group than in the tadalafil monotherapy group, and syncope was more common in the tadalafil-monotherapy group than in the other groups; the incidence of hypotension was similar in the three study groups.

ConclusionsConclusion • Among participants with pulmonary arterial

hypertension who had not received previous treatment, the risk of the composite outcome of clinical failure was significantly lower among those who received initial combination therapy with ambrisentan and tadalafil than among those who received monotherapy with either ambrisentan or tadalafil

Twelve vs 48 months of dual antiplatelet therapy after drug-eluting stent placementThe OPTIDUAL randomized trial

09/12/2015 ESC JOURNAL

Background (1)The long-term risk of very late thrombosis after PCI does not decrease over time

Nearly half of the recurrent MACE after PCI for ACS are associated with non-culprit lesions at the time of PCI

Wenaweser P et al. JACC 2008;52 Stone G et al. N Engl J Med 2011;364

Background (2)DAPT trial: showed a reduction in rates of MACCE and stent thrombosis but an increase in bleeding

Mauri L et al. N Engl J Med 2014;371:2155

Hypothesis

• On a background of aspirin, continuing clopidogrel for up to 48 months would be superior to stopping clopidogrel at 12 months following drug-eluting stent (DES) implantation in reducing net adverse clinical events (composite of death, MI, stroke or major ISTH bleeding)– Randomized, multicentre, open-label study conducted in

58 sites in France (January 2009–January 2013)

Inclusion criteria• Patients with stable

CAD or ACS• With ≥1 lesion with

a significant stenosis in an artery ≥2.25 mm

• Implanted with ≥1 DES of any type

Exclusion criteria• DES implantation in an

unprotected left main coronary artery

• Requirement for oral anticoagulation

• Malignancies or other coexisting conditions associated with a life expectancy of <2 years

Patient selection

DES insertion

12 ± 3 monthsASPIRIN + CLOPIDOGREL

Randomization of patients free of MACCE or

bleed

Follow-up (every 6 months between 12 and 48 months)

ASPIRIN + CLOPIDOGREL

ASPIRIN ALONE

End of the study

0 12 months 48 months

Study design

Methods• Primary endpoint

– Net adverse clinical events: composite of all-cause death, non-fatal MI, stroke, or major bleeding (ISTH classification)

• Secondary endpoints– Individual components of the primary outcome – Stent thrombosis (defined according to the

Academic Research Consortium [ARC])– Repeat revascularization of the treated vessel – Bleeding (ISTH, GUSTO, TIMI, BARC

classifications)

Superiority trial: – 983 patients per arm – 80% power, alpha type-I error of 5%– Significant reduction in the primary composite

outcome at 3 years post-randomization from 7% with aspirin alone to 4% with extended DAPT

Owing to lack of resources and slower enrolment than anticipated, the executive committee and sponsor recommended termination of follow-up at the end of September 2014

Statistical analysis

Patient flow chart (CONSORT)

EXTENDED DAPT GROUPn=695

ASPIRIN GROUPn=690

P value

Age (years), mean (SD) 64.1 (10.8) 64.2 (11.5) 0.88

Women 18.3% 20.7% 0.23

Diabetes mellitus 30.6% 32.2% 0.54

Hypertension 57% 60.4% 0.19

Current/recent smoker 61.2% 57.8% 0.21

Previous PCI 25.9% 27.0% 0.66

Previous MI 17.1% 17.7% 0.78Previous CABG 5.3% 5.1% 0.83

Stroke or TIA 4.2% 3.6% 0.60

Peripheral artery disease

4.9% 6.5% 0.19

Patient baseline characteristics

EXTENDED DAPT GROUP n=695 ASPIRIN GROUP n=690 P value

Indication for PCI

STEMI 10.7% 11.9% 0.47

Non-STEMI 14.2% 17.0% 0.39

Unstable angina 9.5% 9.1% 0.81

Stable angina 34.5% 30.0% 0.07

Silent ischaemia 19.9% 21.9% 0.35

Other 11.2% 10.1% 0.63

Type of DES

Sirolimus 19.9% 17.5% 0.17

Paclitaxel 15.2% 16.0% 0.65

Zotarolimus 8.3% 10.8% 0.05

Everolimus 50.2% 49.2% 0.66

Other 6.4% 6. 5% 0.93

Target vessel

Left main <1% >1% 0.69

LAD 58% 64% 0.007

LCX 33% 31% 0.59

RCA 41% 39% 0.58

Procedural characteristics

65.6%

34.4% 38.0%

62.0%

35.1% 33.5%

EXTENDED DAPT GROUP n=695

ASPIRIN GROUP n=690

P value

Statin 94.4% 93.3% 0.41

ACE inhibitor 75.1% 74.2% 0.71

Proton-pump inhibitor 49.8% 46.8% 0.27

Beta-blocker 78.0% 81.6% 0.09

Calcium-channel inhibitor

30.9% 29.0% 0.43

Aspirin 100% 99.6% 0.12

Daily dose of aspirin at the time of randomization (mg)

0.84

≤100 78.6% 78.2%

101–300 21.4% 21.8%

Treatment at randomization

R 0.75, 95% CI 0.50-1.28P=0.17

5.8%

7.5%

Primary outcome:Composite of death, MI, stroke, major bleed

Components of the primary endpoint

HR 0.65, CI 0.34-1.22 P=0.18

HR 0.69, CI 0.22-2.18 P=0.53

HR 0.67, CI 0.31-1.44 P=0.31

HR 0.98, CI 0.47-2.05 P=0.95

Death Stroke

MI Major bleed

4.2%

6.4%

HR 0.64, 95% CI 0.40-1.02P=0.06

Post-hoc analysis of ischaemic outcomes: death, stroke, or MI

Bleeding eventsExtended-DAPT

groupAspirin group Difference

Percentage points (95% CI)

P value

GUSTO moderate or severe

1.9% 1.7% 0.1 (-1.3 to 1.5) 0.85

Moderate 1.6% 1.2% 0.4 (-0.8 to 1.7) 0.49

Severe 0.4% 0.6% -0.2 (-0.9 to 0.6) 0.72

BARC type 2.6% 2.9% - 0.3 (-2.0 to 1.4) 0.72

2 0.7% 1.0% -0.3 (-1.3 to 0.7) 0.85

3 1.9% 2.0% -0.1 (-1.6 to 1.3) 0.83

5 0.1% 0 0.1 (-0.1 to 0.4) 1.00

TIMI major or minor 2.6% 2.9% -0.3 (-1.4 to 2.0) 0.72

Major 0.6% 0.6% 0.0 (-0.8 to 0.8) 1.00

Minor 2.2% 2.3% -0.1 (-1.7 to 1.4) 0.84

ISTH major 2.0% 2.0% 0.0 (-1.5 to 1.5) 0.98

ISTH moderate 0.9% 1.0% -0.1 (-1.1 to 0.9) 0.77

Meta-analysis of RCTs testing 12 months vs longer DAPT after

DES: Death, stroke, MI

Study limitations

• Only powered to detect major differences in ischaemic and bleeding events

• Termination of the trial before enrolment and follow-up were completed reduced the trial power

• Open-label trial, although all clinical outcomes were adjudicated by an independent clinical event committee blinded to treatment assignment

Conclusions (1)

Extending DAPT duration for up to 48 months

did not achieve statistical superiority

compared with stopping clopidogrel at 12

months with regards to net adverse clinical

outcomes, in patients free of MACCE and

major bleed 12 months after stent implantation

Conclusions (2) • Borderline but non-statistically significant

reduction in post-hoc analysis of

ischaemic outcomes with extended DAPT

• No apparent increase in bleeding and all-

cause mortality with extended DAPT

TOTAL TRIAL

BACKGROUND

TAPAS TRIAL

Results from TASTE(september 18, 2014)

NEJM

Routine thrombus aspiration before PCI in patients with STEMI did not reduce the rate of death from any cause or the composite of death from any cause, rehospitalization for myocardial infarction, or stent thrombosis at 1 year

INCLUSION CRITERIA• Patients with

STEMI who were referred for primary PCI within 12 hours after the onset of symptoms were eligible to participate in the trial.

EXCLUSION CRITERIA• Patients who had

undergone previous coronaryartery bypass grafting or those who had received fibrinolytic therapy were not eligible

TOTAL TRIAL

Follow-up

THROMBECTOMY+ PCI

End of the study

Study design

PCI ALONE

Randomisation done in 1:1 ratio 0

Mean follow up 180 days Total of 10,732 patients

5372 patients

5360 PATIENTS

• Primary outcome • composite of death from

cardiovascular causes, recurrent myocardial infarction, cardiogenic shock, or New York Heart Association (NYHA) class IV heart failure within 180 days. The key

• Safety outcome was stroke within 30 days

LIMITATIONS• First: The treating interventional cardiologists

were aware of study group assignments. (BIAS)• Second: study included pt with less thrombus

burden also• Third: This trial evaluated a strategy of routine

upfront thrombectomy versus PCI alone with thrombectomy reserved as bailout; it did not study the effect of selective use of thrombectomy versus no thrombectomy

• Conclusion:• In patients with STEMI who were undergoing PCI, a

strategy of routine manual thrombectomy did not reduce the risk of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or class IV heart failure within 180 days, as compared with a strategy of PCI alone with only bailout thrombectomy.

• Routine thrombectomy was associated with an increased rate of stroke within 30 days.

• The potential benefit of dual antiplatelet therapy beyond 1 year after a myocardial infarction has not been established

Inclusion criteria• Men and women >50 years • Documented history of presumed

spontaneous MI with their most recent MI occurring 1 to 3 years prior to randomization and have at least 1 of the following risk factors: − Age ≥65 years

• − Diabetes mellitus requiring medication

• −Documented history of a second prior presumed spontaneous MI (>1 year ago)

• − Angiographic evidence of multivessel coronary artery disease (CAD)

• Chronic, non-end stage renal ds• Able to take ASA 75-150 mg/d

Exclusion criteria• Planned use of ADP receptor

blockers • Planned coronary,

cerebrovascular, or peripheral arterial revascularization

• Need for chronic oral anticoagulant therapy or chronic LMWH

• Ischemic stroke <14 days• Liver and renal failure on HD• Pregnancy/lactation• Life expectancy <1 yr• CABG in last 5 yr• h/o IC bleed or major Sx <30 day

or GI bleed <6 mnths

Patient selection

Primary outcomes• Composite of

cardiovascular death, myocardial infarction, or

• Stroke . Secondary outcomes• Cardiovascular death

and • Death from any cause

• Primary safety end point • Thrombolysis in

Myocardial Infarction (TIMI) major bleeding

• Secondary safety endpoint

• Intracranial hemorrhage• Fatal bleeding

Protocol Randomised in 1:1:1 fashion

Kaplan–Meier Rates of Cardiovascular Death, Myocardial Infarction, and Stroke through 3 Years, According to Study Group.

Bonaca MP et al. N Engl J Med 2015;372:1791-1800

Hazard Ratios and Rates of the Primary End Point and Individual Components for Each Dose of Ticagrelor and for the Two Doses Pooled.


Safety End Points as 3-Year Kaplan–Meier Estimates.


Conclusions • The rates of bleeding and dyspnea were numerically

lower with the 60-mg dose of ticagrelor than with the 90-mg dose, resulting in a lower rate of discontinuation of the study drug and a better safety profile with the 60-mg dose.

• Thus, in general, the 60-mg dose may offer a more attractive benefit–risk profile, although these differences were not significant

• In conclusion, the addition of ticagrelor, at a dose of 90 mg twice daily or 60 mg twice daily, to low-dose aspirin reduced the risk of cardiovascular death, myocardial infarction, or stroke and increased in the risk of TIMI major bleeding among patients who had had a myocardial infarction 1 to 3 years earlier.

• Background• Dual antiplatelet therapy is recommended

after coronary stenting to prevent thrombotic

• complications, yet the benefits and risks of treatment beyond 1 year are uncertain.

• Patients were enrolled after they had undergone a coronary stent procedure in which a drug-eluting stent was placed. After 12 months of treatment with a thienopyridine drug (clopidogrel or prasugrel) and aspirin, patients were randomly assigned to continue receiving thienopyridine treatment or to receive placebo for another 18 months; all patients continued receiving aspirin.

End points • The coprimary

efficacy end points were stent thrombosis and major adverse cardiovascular and cerebrovascular events (a composite of death, myocardial infarction, or stroke) during the period from 12 to 30 months.

• The primary safety end point was moderate or severe bleeding

• Conclusions• Dual antiplatelet therapy beyond 1 year

after placement of a drug-eluting stent, as compared with aspirin therapy alone, significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding.

Land mark trails of 2014

Valsartan/sacubitril (codenamed LCZ696) is an investigational combination drug consisting of two antihypertensives in a 1:1 mixture by molecule count

Eligibility requirements an age of at least 18 years, • (NYHA) class II, III, or IV

symptoms, EF< 40% • BNP level of at least 150 pg/ml

(OR [NT-proBNP] level ≥600 pg/ml)or, if they had been hospitalized for heart failure within the previous 12 months, a BNP of at least 100 pg/ml (or an NT-proBNP≥400 pg/ml).

• Patients taking any dose of an ACE inhibitor or ARB were considered for participation, but for at least 4 weeks before screening, patients were required to take a stable dose of a beta-blocker and an ACE inhibitor (or ARB) equivalent to at least 10 mg of enalapril daily.

Exclusion criteria • Symptomatic hypotensionSBP 100

mm Hg at screening or 95 mm Hg at randomization,

• eGFR below 30 ml/min/1.73 of BSA at screening or at randomization or a decrease in the eGFR of more than 25% (which was amended to 35%) between screening and randomization,

• a serum potassium level of more than 5.2 mmol/lat screening (or above 5.4 mmol per liter at randomization),

• history of angioedema or unacceptable side effects during receipt of ACE inhibitors or ARBs

Land mark trails of 2014

conclusion• In, angiotensin receptor–neprilysin inhibition with

LCZ696 was superior to ACE inhibition alone in reducing the risks of death and of hospitalization for heart failure.

• The magnitude of the beneficial effect of LCZ696, as compared with enalapril, on cardiovascular mortality was at least as large as that of long-term treatment with enalapril, as compared with placebo.

• This robust finding provides strong evidence that combined inhibition of the angiotensin receptor and neprilysin is superior to inhibition of the renin–angiotensin system alone in patients with chronic heart failure.

Estimating the Long-Term Treatment Benefits of Sacubitril–Valsartan

• To estimate the long-term treatment effects of sacubitril– valsartan versus enalapril, they derived actuarial estimates of age-specific event rates and expected survival times using data regarding the age at randomization and the age at the time of an outcome event from the PARADIGM-HF trial.

Claggett B et al. N Engl J Med 2015;373:2289-2290.

Probability of Death from Any Cause or the Primary End Point Extrapolated from the PARADIGM-HF Trial, According to Age Group.

• The protective effects of sacubitril–valsartan remain consistent with long-term use, the available follow up data estimate that treatment with sacubitril–valsartan would result in a projected benefit of 1 to 2 years of increased life expectancy and survival free from heart failure for patients such as those in the PARADIGM-HF trial.

• Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin– kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in short-term studies.

Follow-up

Evalocumab group

End of the studyStudy design

Standard therapy

Randomisation done in 2:1 ratio 0 Mean follow up

11.1 months.

Total of 4465 patients

2976 patients

1489 PATIENTS

Evalocumab 420mg s/c once in a month

Evalocumab 140mg s/c every 2 weeks or 420mg /month

• In conclusion, patients who had previously participated in 12 shorter-term parent trials of the PCSK9 inhibitor evolocumab underwent repeat randomization to receive either evolocumab or standard therapy in the OSLER program.

• Evolucumab reduced levels of LDL cholesterol by 61% by 12 weeks, with sustained reduction through the median 11-month follow- up.

• In a prespecified exploratory analysis, there was evidence of a reduction in the rate of cardiovascular events among patients receiving evolocumab

• Clinical Inclusion Criteria:• Patient must have a diagnosis

of diabetes mellitus (Type 1 or Type 2) defined according to the American Diabetes Association

• Symptomatic coronary artery disease.

• Angiographic Inclusion Criteria:

• Lesions 34 mm or less in length and a reference-vessel diameter between 2.25 mm and 4.0 mm

• Clinical Exclusion Criteria• LVEF <30%• Acute or chronic Kidney

disease• Serious medical illness with ife

expectancy <12 mnths• Angiographic Exclusion

Criteria:• LMCA stenting• Venous graft stenting• Bifurcation stenting• ISR

• Primary end point • Target-vessel failure was

defined as a• composite of cardiac

death, • target-vessel myocardial

infarction, or • ischemia-driven target-

vessel revascularization

• Secondary end points• ischemia-driven target-

lesion revascularization,• target-vessel

revascularization, the composite of cardiac death or target-vessel myocardial infarction, major adverse cardiac events.

Clinical Outcomes.

Kaul U et al. N Engl J Med 2015;373:1709-1719

Prespecified Subgroup Analyses of the Primary End Point.

Kaul U et al. N Engl J Med 2015;373:1709-1719

Conclusion • Study did not show noninferiority of paclitaxel-

eluting stents to everolimus eluting stents in patients with coronary artery disease and diabetes mellitus. Everolimus-eluting stents were superior to paclitaxel-eluting stents with regard to several end points, including target-vessel failure, myocardial infarction, and stent thrombosis.

A noniferiority trial

• Inclusion criteria• 18 years of age or older with

myocardial ischemia who were undergoing PCI for one or two new native coronary artery lesions in separate epicardial coronary vessels were eligible for enrollment.

• Each lesion was required to be no more than 24 mm in length with a reference-vessel diameter of 2.5 to 3.75 mm on visual assessment.

• Exclusion criteria• Patients with acute

myocardial infarction and specific complex lesion features were excluded

• The primary end point was target-lesion failure (a composite of cardiac death, target-vessel myocardial infarction, or ischemia-driven target-lesion revascularization) at 1 year.

• Secondary end points were the 1-year rates of angina (excluding symptoms through the time of hospital discharge), all revascularization, and ischemia-driven target-vessel revascularization

Target-Lesion Failure at 1 Year.

Ellis SG et al. N Engl J Med 2015;373:1905-1915

Subgroup Analyses of Target-Lesion Failure at 1 Year.

Ellis SG et al. N Engl J Med 2015;373:1905-1915

• The Absorb everolimus-eluting bioresorbable vascular scaffold was within the prespecified noninferiority margin in comparison with the Xience everolimus-eluting cobalt–chromium stent for the primary end point of target lesion failure at 1 year.

• Although 1-year thrombosis rates were not significantly different between the Absorb scaffold and the Xience stent, subacute thrombosis between 1 day and 30 days was more common with the Absorb scaffold in the intention-to-treat analysis

Conclusion • In conclusion, in this large-scale

randomized trial, treatment of noncomplex coronary lesions with the Absorb everolimus-eluting bioresorbable vascular scaffold was within the prespecified range for noninferiority to the Xience everolimus-eluting cobalt–chromium stent with regard to target-lesion failure at 1 year.

An observational study

From New York University School of Medicine,New York (S. Bangalore, Y.G., S.Blecker, J.X.); and the School of PublicHealth, State University of New York atAlbany, Albany (Z.S., E.L.H.). Address reprintrequests to Dr. Bangalore at the CardiovascularClinical Research Center, NewYork University School of Medicine, NewYork, NY 10016, or at [email protected] article was published on March 16,2015, at NEJM.org.

• Selexipag, an oral selective IP prostacyclin-receptor agonist, was shown to be beneficial in the treatment of pulmonary arterial hypertension.

Inclusion criteria• The study population included patients 18 to 75 years of age who

had idiopathic or heritable pulmonary arterial hypertension or pulmonary arterial hypertension associated with human immunodeficiency virus infection, drug use or toxin exposure, connective tissue disease, or repaired congenital systemic-to-pulmonary shunts.

• Confirmation of the diagnosis by means of right heart catheterization was required before screening.

• Patients were required to have a pulmonary vascular resistance of at least 5 Wood units (400 dyn · sec · cm−5) and a 6-minute walk distance of 50 to 450 m.

• Patients who were not receiving treatment for pulmonary arterial hypertension and those who were receiving an endothelin- receptor antagonist, a phosphodiesterase type 5 inhibitor, or both at a dose that had been stable for at least 3 months were eligible for enrollment.

• Patients who were receiving prostacyclin analogues were not eligible.

Enrollment, Randomization, and Follow-up.

Sitbon O et al. N Engl J Med 2015;373:2522-2533

• Primary endpoint• Composite of death or • PAH complications that

include 1. Disease progression 2. worsening PAH, req

hospitalisation3. Initiation of parenteral

prostanoid therapy or4. long-term oxygen

therapy, or 5. Need for lung

transplantation or BAS.

• Secondary end points• in 6-minute walk

distance from baseline to week 26.

• worsening NYHA class• death due to PAH or• Hospitalization due to

PAH worsening • death from any cause up

to the end of the study

Primary Composite End Point.

End Points Related to Pulmonary Arterial Hypertension and Death.


Most Frequent Adverse Events and Abnormal Laboratory Results.


• In conclusion, among patients with pulmonary arterial hypertension, the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower among patients who received selexipag than among those who received placebo.

• There was no significant difference in mortality between the two study groups.

ANNEXA-A and ANNEXA-R

• Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs.

• Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors.

ANNEXA-A and ANNEXA-Rland mark trials in 2015

• Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs.

• Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors.

land mark trials in 2015

Take home message 1. Intensive blood pressure control resulted in

lower rates of fatal and nonfatal major cardiovascular events and death from any cause.

2. When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes.

3. The use of evolocumab or arilocumab plus standard therapy, as compared with standard therapy alone, significantly reduced LDL cholesterol levels and reduced the incidence of cardiovascular events


• The rates of major adverse cardiovascular events and net adverse clinical events were not significantly lower with bivalirudin than with unfractionated heparin.

• Routine manual thrombectomy, as compared with PCI alone, did not reduce the risk of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or NYHA class IV heart failure within 180 days.


• Everolimus-eluting stents were superior to paclitaxel-eluting stents with regard to several end points, including target-vessel failure, myocardial infarction, and stent thrombosis.

• The addition of ticagrelor, at a dose of 90 mg twice daily or 60 mg twice daily, to low-dose aspirin reduced the risk of cardiovascular death, myocardial infarction, or stroke and increased in the risk of TIMI major bleedingland mark trials in 2015

• The addition of ticagrelor, at a dose of 90 mg twice daily or 60 mg twice daily, to low-dose aspirin reduced the risk of cardiovascular death, myocardial infarction, or stroke and increased in the risk of TIMI major bleeding among patients who had had a myocardial infarction 1 to 3 years earlier.

• The protective effects of sacubitril–valsartan remain consistent with long-term use, the available follow up data estimate that treatment with sacubitril–valsartan would result in a projected benefit of 1 to 2 years of increased life expectancy and survival free from heart failure for patients such as those in the PARADIGM-HF trial.


•Thank you


land mark trials 2015

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