JOURNAL CLUB

August 28,2016

INTRODUCTION

• Obstructive sleep apnea causes –1. Episodic hypoxemia2. Nocturnal sympathetic nervous system activation 3. Elevates blood pressure and4. Markers of oxidative stress, inflammation, and

hypercoagulation.

• Large negative intrathoracic pressure swings also impose mechanical stress on the heart and great vessels.

• 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 (CPAP)

1. Lowers SBP by 2 to 3 mm Hg in patients with normotensive OSA

2. by 6 to 7 mm Hg in patients with resistant hypertension,

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 OSA.

METHODS

STUDY DESIGN

• The SAVE study was an:1. international, 2. multicenter,3. randomized, 4. parallel-group, 5. open-label trial, 6. with blinded end-point assessment.

INCLUSION CRITERIA

• Patients were recruited at 89 clinical centers in 7 countries;

1. an age between 45 and 75 years,2. a diagnosis of coronary artery disease or

cerebrovascular disease,3. a diagnosis of moderate-to-severe obstructive

sleep apnea

MODERATE-TO-SEVEREOBSTRUCTIVE 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.

EXCLUSION CRITERIA

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).

RANDOMIZATION AND INTERVENTIONS

"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 sleep apnea.

• Clinic visits were scheduled for all participants at 1, 3, 6, and 12 months and annually thereafter.

STUDY MEASURMENTS

• 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 recorded.

• At randomization, at 6 months, and at 2 and 4 years, anthropometric measurements were obtained in all participants.

• 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 infarction),

2. stroke,3. hospitalization for heart failure, acute coronary

syndrome (including unstable angina), or transient ischemic attack.

• Secondary cardiovascular end points included:1. Revascularization procedures,2. New onset atrial fibrillation,3. New-onset diabetes mellitus, 4. Death from any cause.

STATISTICAL ANALYSIS

• 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 events.

RESULTS

The mean duration of follow-up was 3.7 years.

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 night.

• 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 night)during follow-up.

• 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.

DISCUSSION

• 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.

LIMITATIONS

• For several of the participating countries, the diagnosis and treatment of sleep apnea were not well established in clinical practice when the trial began.

• However, before trial recruitment, investigators expended substantial time and effort in conducting training workshops for investigators and study coordinators.

• 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 were excluded.

Conclusion

• 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 events.

• Though it significantly reduced sleepiness and other symptoms of OSA and improved quality-of-life measures.

August 28,2016

INTRODUCTION

• 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 pacemaker.

• 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.

METHODS

TRIAL OVERSIGHT

• 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.

INCLUSION CRITERIA

• 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 upgraded.

EXCLUSION CRITERIA

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.

TRIAL PROCEDURES

• Participants were randomly assigned in a 1:1 ratio to either the ICD group or the control group (usual clinical care).

• The decision to implant a CRT device had to be made before randomization.

• 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.

OUTCOMES

• Primary outcome – death from any cause• Secondary outcomes – 1. Sudden cardiac death, 2. Resuscitated cardiac arrest or sustained

ventricular tachycardia, 3. Change from baseline in quality of life

STATISTICAL ANALYSIS

• The baseline characteristics were compared between the treatment groups with the use of chi-square and Wilcoxon tests.

• Outcomes were analyzed with the use of time-to-event methods.

• 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).

RESULTS

FOLLOW-UP AND OUTCOMES

The median follow-up period was 67.6 months

Time-to-Event Curves for Death from Any Cause, CardiovascularDeath, and Sudden Cardiac Death

SUBGROUP ANALYSIS

DISCUSSION

• 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 survival benefit;

• 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 antagonists.

• Investigators did not find a difference in the relative effect of an ICD between patients who received CRT and patients who did not.

• 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 heart failure.

• 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 received a mineralocorticoid-receptor antagonist, and no patients received concomitant CRT.

• The DEFINITE trial, which enrolled patients between 1998 and 2002, included a larger proportion of patients who received beta-blockers (85%) but, again, no patients who received CRT.

CONCLUSION

• 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.