• Obstructive sleep apnea causes –
1. Episodic hypoxemia
2. Nocturnal sympathetic nervous system activation
3. Elevates blood pressure and
4. Markers of oxidative stress, inflammation, and
• Large negative intrathoracic pressure swings also
impose mechanical stress on the heart and great
• Various cohort studies have shown an association
between obstructive sleep apnea and cardiovascular
events, particularly stroke.
• Randomized,controlled trials have shown that
treatment with continuous positive airway pressure
1. Lowers SBP by 2 to 3 mm Hg in patients with
2. by 6 to 7 mm Hg in patients with resistant
3. improves endothelial function,
4. increases insulin sensitivity.
• Observational clinical studies have shown that the
use of CPAP is associated with
1. lower rates of cardiovascular complications
2. death from cardiovascular causes, especially among
patients who are adherent to treatment.
• SLEEP APNEA CARDIOVASCULAR ENDPOINTS (SAVE)
STUDY, a secondary prevention trial - designed to
evaluate the effectiveness of CPAP in reducing the
rate of cardiovascular events among patients with
• The SAVE study was an:
5. open-label trial,
6. with blinded end-point assessment.
• Patients were recruited at 89 clinical centers in 7
1. an age between 45 and 75 years,
2. a diagnosis of coronary artery disease or
3. a diagnosis of moderate-to-severe obstructive
OBSTRUCTIVE SLEEP APNEA
• Defined as an OXYGEN DESATURATION INDEX (the
number of times per hour during the oximetry
recording that the blood oxygen saturation level
drops by ≥4 percentage points from baseline) of at
least 12, was established with the use of a home
sleep study screening device.
1. Patients reporting severe daytime sleepiness
(Epworth Sleepiness Scale score >15);
2. Patients having an increased risk of an accident
from falling asleep,
3. Patients having very severe hypoxemia (oxygen
saturation <80% for >10% of recording time),
4. Patients having pattern of Cheyne–Stokes
respiration on the nasal pressure recording.
• Potential participants were required to have a
minimum level of adherence to CPAP therapy, which
was defined as an average of 3 hours per night,
during a 1-week run-in period in which sham CPAP
was used (i.e., CPAP at subtherapeutic pressure).
"Usual care" consisted of advice on healthy sleep habits and lifestyle changes along
with cardiovascular risk management.
• The patients who were assigned to receive mask-
delivered CPAP treatment were provided with an
automated positive airway pressure machine.
• Concomitant management of cardiovascular risk
factors were performed.
• All participants were given advice on healthful sleep
habits and lifestyle changes to minimize obstructive
• Clinic visits were scheduled for all participants at 1,
3, 6, and 12 months and annually thereafter.
• At randomization and at each follow-up visit,
participants’ BP and HR was measured.
• Among the participants in the CPAP group, data on
adherence to the use of the CPAP device were
• At randomization, at 6 months, and at 2 and 4 years,
anthropometric measurements were obtained in all
• Questionnaires for assessment of symptoms of OSA
were given at follow up(snoring, witnessed episodes
of apnea, and degree of sleepiness according to the
Epworth Sleepiness Scale score);
• The Medical Outcomes Study 36-Item Short-Form
Health Survey(SF-36; scores range from 0 to 100,
with higher scores indicating better quality of life);
• Hospital Anxiety and Depression Scale (on which
anxiety and depression scores range from 0 to 21,
with higher scores indicating more symptoms) for
assessment of mood.
• The end-of-study visits were conducted from September
2015 through January 2016
STUDY END POINTS
• The primary end points were composite of death
from any cardiovascular cause;
1. myocardial infarction (including silent myocardial
3. hospitalization for heart failure, acute coronary
syndrome (including unstable angina), or transient
• Secondary cardiovascular end points included:
1. Revascularization procedures,
2. New onset atrial fibrillation,
3. New-onset diabetes mellitus,
4. Death from any cause.
• The primary analysis was an unadjusted
survival analysis performed according to the
intention-to-treat principle with the use of
Cox proportional- hazards regression models
that was based on positively adjudicated
INTERVENTION ADHERENCE, MEDICATIONS,
AND LIFESTYLE FACTORS
• The mean duration of use of the sham CPAP device
during the 1-week run-in phase was 5.2 hours per
• In the CPAP group, the mean (±SD) duration of
adherence to CPAP therapy in the first month of
treatment was 4.4±2.2 hours per night, which
decreased to 3.5±2.4 hours per night by 12 months
and remained relatively stable thereafter.
• The residual apnea–hypopnea index during CPAP use,
averaged 3.7 events per hour, which indicated good
control of OSA with CPAP.
• Of the 1346 patients in the CPAP group, 566 (42%) had
good adherence to treatment (≥4 hours per
• No significant differences were observed between the
two groups in the use of medications for diabetes
mellitus and cardiovascular conditions, in lifestyle
factors including diet and smoking, and in body-mass
index from baseline to the end of the study.
• Trial showed that the risk of serious cardiovascular
events was not lower among patients who received
treatment with CPAP in addition to usual care than
among those who received usual care alone.
• Treatment with CPAP was associated with a greater
reduction in symptoms of daytime sleepiness and
with improved health-related quality of life, mood,
and attendance at work.
• Three other randomized trials and
• Two studies — a multicenter study from Spain (725
patients) that compared CPAP with usual care with
OSA and a single-center study involving 224 patients
showed no difference in composite cardiovascular
end points over several years of follow-up.
• Although in adjusted analyses, both studies reported
better outcomes among patients who were adherent
to CPAP therapy (≥4 hours per night) than among
patients who did not receive CPAP or who used CPAP
less than 4 hours per night.
• For several of the participating countries, the
diagnosis and treatment of sleep apnea were not
well established in clinical practice when the trial
• However, before trial recruitment, investigators
expended substantial time and effort in conducting
training workshops for investigators and study
• To reduce the risk of recruiting patients with pre-
dominantly central apnea rather than obstructive
sleep apnea, patients with overt heart failure and
patients in whom the nasal pressure signals showed
a predominant pattern of Cheyne–Stokes respiration
• In a large group of adults with both cardiovascular
disease and moderate-to severe OSA, the use of
CPAP therapy had no significant effect on the
prevention of recurrent serious cardiovascular
• Though it significantly reduced sleepiness and other
symptoms of OSA and improved quality-of-life
• Prophylactic implantation of an implantable
cardioverter–defibrillator (ICD) is a class 1
recommendation for patients with heart failure and
reduced left ventricular systolic function in both
european and us guidelines.
• In the case of patients without ischemic heart
disease, no single trial has shown a convincing effect
on total mortality.
• The Comparison of Medical Therapy, Pacing, and
Defibrillation in Heart Failure(COMPANION) study,
randomly assigned 1520 patients with (NYHA) class
III or IV heart failure to receive medical therapy, a
cardiac resynchronization therapy (CRT) pacemaker,
or a CRT defibrillator, showed significantly lower all-
cause mortality in association with a CRT defibrillator
than with medical treatment alone, but a CRT
defibrillator was not shown to be superior to a CRT
• The Sudden Cardiac Death in Heart Failure Trial (SCD-
HeFT) was the only randomized trial involving
patients with nonischemic systolic heart failure in
which a significant benefit with regard to all-cause
mortality has been reported in association with the
implantation of an ICD.
• However, the positive effect of ICD treatment was
confined to patients in NYHA class II.
• Given the limited evidence of a benefit from the
implantation of an ICD in patients with chronic
nonischemic heart failure, investigators conducted a
randomized trial in which patients with
1. chronic symptomatic heart failure,
2. reduced ejection fraction,
3. increased levels of natriuretic peptide with or
without a need for CRT were randomly assigned
either to receive or not to receive an ICD.
• The Danish Study to Assess the Efficacy of ICDs in
Patients with Non-ischemic Systolic Heart Failure on
Mortality (DANISH) was an investigatorinitiated
multicenter, randomized, unblinded, controlled trial
that was conducted at all centers in Denmark at
which ICDs were implanted.
• Symptomatic patients (NYHA class II or III, or NYHA class
IV if CRT was planned);
• Nonischemic systolic heart failure (left ventricular
ejection fraction ≤35%);
• An increased level (>200 pg per milliliter) of N-terminal
pro–brain natriuretic peptide (NT-proBNP).
• A nonischemic cause of heart failure was usually
determined by coronary angiography, although a normal
computed tomographic (CT) angiogram or nuclear
myocardial perfusion imaging study was acceptable.
• Patients with an existing conventional pacemaker or
CRT pacemaker device could be included if the
patients were willing to have the device changed or
1. Patients with permanent atrial fibrillation
with a resting heart rate higher than 100
beats per minute.
2. Patients with renal failure that was being
treated with dialysis.
• Participants were randomly assigned in a 1:1 ratio to
either the ICD group or the control group (usual
• The decision to implant a CRT device had to be made
• Implantation of an ICD (or a CRT pacemaker or CRT
defibrillator) was planned to be performed no later
than 4 weeks after randomization;
• All patients were seen at follow-up visits after 2
months and every 6 months thereafter until the end
of the trial.
• Primary outcome – death from any cause
• Secondary outcomes –
1. Sudden cardiac death,
2. Resuscitated cardiac arrest or sustained
3. Change from baseline in quality of life
• The baseline characteristics were compared between
the treatment groups with the use of chi-square and
• Outcomes were analyzed with the use of time-to-
• Kaplan–Meier plots were calculated for total
mortality, and cumulative incidence curves were
calculated for events with competing risk (sudden
cardiac death and cardiovascular death).
• Investigators found that implantation of an ICD in
patients who had heart failure that was not caused
by ischemic heart disease did not provide an overall
• Although the risk of sudden cardiac death was halved
with an ICD.
• Younger patients may have a survival benefit in
association with ICD implantation
• All time-to-event curves appeared to diverge during
the initial 5 years of the trial and then to converge.
• This trial event rate was lower than that observed in
older studies, which reflects the fact that study
population consisted of:
• Stable OPD patients treated according to guidelines
with most patients receiving beta-blockers and
inhibitors of the renin–angiotensin system and 60%
of the patients receiving mineralocorticoid-receptor
• Investigators did not find a difference in the relative effect of
an ICD between patients who received CRT and patients who
• Also in the COMPANION trial, the overall difference in
mortality between the CRT defibrillator group and the CRT
pacemaker group was not tested statistically.
• But later analyses of the data by independent authors, the
crude P value based on overall mortality in the CRT
pacemaker group versus the CRT defibrillator group was
calculated as 0.12.
• At present, it is therefore unclear whether patients who are
eligible for CRT should routinely receive an ICD.
• The side effects associated with device implantation
in this trial were not trivial.
• Device related infections were frequent.
• In a recent study, major device-related complications
occurred within the first 6 months after implantation
in approximately 6% of patients who received an ICD
and 11% of patients who received a CRT defibrillator.
• Rates of inappropriate shocks or inappropriate
antitachycardia pacing have decreased in recent
years with the use of less aggressive ICD settings.
• 6% of patients have inappropriate shocks within 2.5
years after implantation of a dual-chamber ICD.
• These figures are similar to the 5.9% of patients who
received inappropriate shocks in DANISH trial.
• The DANISH trial adds to the available body of data
to consider in formulating the indications for ICD
implantation in patients with nonischemic systolic
• Currently AHA guidelines, ICD implantation for
primary prevention of SCD in patients with
symptomatic systolic heart failure is a class 1A
recommendation, with no differentiation between
patients with ischemic and nonischemic causes with
reference to SCD-HeFT trial.
• In the European guidelines, ICD implantation
is a class 1B recommendation for patients with
nonischemic heart failure with reference to
DEFINITE trial .
• SCD-HeFT enrolled
patients between 1997
and 2001, and only 69%
of enrolled patients
received beta-blockers at
baseline, 20% of patients
receptor antagonist, and
no patients received
• The DEFINITE trial, which
between 1998 and 2002,
included a larger
proportion of patients
who received beta-
blockers (85%) but, again,
no patients who received
• Prophylactic ICD implantation in patients with
symptomatic systolic heart failure that was
not caused by coronary artery disease was not
found to reduce long-term mortality.