More from the ESC Barcelona Congress – Improvements shown with CRT treatment in less severe heart failure patients

Asymptomatic or mildly symptomatic cardiac patients randomised to an implanted cardiac resynchronisation device with defibrillator (CRT-D) have a 34% lower risk of heart failure or death than those receiving a standard implanted cardioverter defibrillator (ICD-only) (HR 0.66, p=0.001), according to results from the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronisation Therapy) study.

The MADIT-CRT study was a randomised trial designed to determine if CRT-D therapy would reduce the primary endpoint (all-cause mortality or heart failure events, whichever occurred first) when compared to patients receiving ICD-only therapy. The study population involved cardiac patients in New York Heart Functional Class I or II (no or mild symptoms) who had either ischaemic or non-ischaemic heart disease with left ventricular dysfunction (ejection fraction <30%) and QRS duration of >130ms on ECG.

Cardiac resynchronisation therapy (CRT) with or without a defibrillator is indicated for use in patients with severe heart failure (New York Heart Association Class III/IV), and CRT has been shown to reduce symptoms, mortality and hospitalisation in very sick cardiac patients. The question that remained was whether CRT would improve heart function and slow or prevent the development of heart failure in the less severe NYHA class I/II cardiac patients (moderately high risk, but with no or mild symptoms) by intervening early in the course of the disease before the development of advanced symptoms.

The MADIT-CRT trial enrolled and followed 1820 patients from 110 centers in Europe, Canada, and the USA during a 4.5-year period between December 2004 and 22 June 2009, when the trial was officially ended because of the superiority of the cardiac resynchronisation therapy (p=0.001). Patients were randomised in a 3:2 fashion to receive either CRT-D or ICD alone, and all patients received optimal medical therapy for heart failure during the trial.

The superiority of CRT-D therapy was found to be present in all patient sub-groups, including those with ischaemic and non-ischaemic types of heart disease, as well as in males and females, younger and older patients, and those with mild and more advanced heart dysfunction.

Commenting on the results, the study’s principal investigator, Professor Arthur J Moss from the University of Rochester Medical Center, New York, USA, said: “Cardiac resynchronisation therapy was dramatically effective in this large study population, with a 34% reduction in the risk of all-cause mortality or heart failure. The benefit is dominated by a 41% reduction in heart failure events. This results validate a new indication for cardiac resynchronisation therapy in the prevention of heart failure in at-risk asymptomatic or mildly symptomatic cardiac patients. It seems likely that this preventive CRT-D therapy will have widespread application and utilisation.”

Cardiac Resynchronisation Therapy: Reverse Trial

Cardiac resynchronisation therapy (CRT) is a proven therapy indicated for patients with moderate to severe heart failure. Additional 24-month clinical data presented at the Barcelona ESC Congress on the European cohort of 262 patients in the REVERSE (Resynchronisation Reverse Remodeling in Systolic Left Ventricular Dysfunction) trial, sponsored by Medtronic, Inc., provides a deeper understanding of how CRT improves the function of the heart, including reduction in heart size and improvements in pumping efficiency, in certain heart failure patients with mild symptoms.

With 610 patients studied, REVERSE is the first large-scale, global, randomized, double-blind trial to demonstrate the impact of CRT in mild heart failure patients or asymptomatic patients who previously had heart failure symptoms. As previously reported, the trial did not meet statistical significance for its primary endpoint – a heart failure Clinical Composite Score (a measure of both subjective and objective assessments) at 12 months. However, the European cohort, which was followed through 24 months, did demonstrate statistical significance.

Three sessions featuring 24-month REVERSE data were presented during the European Society of Cardiology congress in Barcelona:

• Clinical Trial Update: “Cardiac Resynchronisation Therapy Induces Major Structural and Functional Reverse Remodeling in Mild Heart Failure,” by Dr. Stefano Ghio of Policlinico San Matteo in Pavia, Italy.
• “CRT in Mild Heart Failure: Differences in Outcomes Between NYHA Class I and II Patients Over 24 Months of CRT,” by Prof. Cecilia Linde of Karolinska University Hospital in Stockholm.
• “Relationship of QRS Duration to Reverse Remodelling with CRT in Mild Heart Failure Over Two Years,” by Michael Gold, M.D. of the Medical University of South Carolina in Charleston, S.C.

“The REVERSE 24-month results, presented at ACC 2009, suggest that CRT may improve clinical outcomes and ventricular function,” said Prof. Ghio. “While we’ve already seen improvement in more symptomatic patients with CRT, the additional analyses presented here at ESC give us valuable insights about ventricular structure and how CRT might be used to modify disease progression and help heart failure patients with mild symptoms.”

Key Findings

Additional 24-month results from the European cohort of the REVERSE trial indicate that CRT may prevent or slow the progression of disease in asymptomatic or mildly symptomatic heart failure patients.

• CRT reduced the need for heart failure hospitalisation in NYHA Class II patients (p=0.004) (Linde).
• The trial demonstrated a statistically significant reduction in heart size (left ventricular end systolic volume index, or LVESVi), as measured by cardiac ultrasound, improving its function and helping the heart pump more efficiently in patients receiving CRT (p<0.0001). This trend was first seen at 12 months, and continued at 24 months (Ghio).
• There was a statistically significant increase in LVEF: from 28.1 percent to 34.8 percent in patients receiving CRT, compared to 27.8 percent to 29.9 percent in patients not receiving CRT (p=0.002) (Ghio).
• CRT reduced left ventricular volumes throughout the range of QRS duration (the length of time for the heart to contract) (p<0.0001), and CRT effectiveness was greater as QRS duration widened (Gold).

Currently, CRT is not approved in the United States for use in the mildly symptomatic or asymptomatic patients who were shown to benefit from CRT in this trial.

Trialists believe that the REVERSE trial continues to uncover valuable data for the clinical community to inform the treatment of heart failure patients.

PreSCD II registry shows mortality reduction after non-acute ICD implantation in myocardial infarction survivors

The goals of the PreSCD II (Prevention of Sudden Cardiac Death II) registry are to collect recent data on patients with high risk for sudden cardiac death after a heart attack and to describe their prognosis in relation to initial left ventricular ejection fraction (LVEF) as the primary risk marker.

Findings from the latest PreSCD II analysis show that patients protected against sudden cardiac death by an implantable cardioverter defibrillator (ICD) one month or more after MI showed a non-significant (p=0.053) 44% lower mortality than comparable patients without an ICD. In those patients with severely reduced heart function (ejection fraction of 30% or less) mortality was reduced by 47%, with borderline significance (p=0.07). “Remarkably,” says investigator Professor Heinz Völler from the Klinik am See in Ruedersdorf, Germany, “we observed in the data a survival benefit that increased with the time interval between MI and ICD implantation.”

Based on the MADIT II trial results, ejection fraction is predominantly used for risk stratification in MI patients to determine implantation of an ICD. The PreSCD II analysis was thus stratified according to patients who presented with a severely reduced ejection fraction (≤30%), a moderately impaired (31-40%) or normal heart function. “We were surprised that in the high risk group of patients with severely reduced heart function, which comprised only 2.5% of the registry population, only 22% of them were protected by an ICD as primary prevention of sudden cardiac death,” said Professor Völler.

Between December 2002 and May 2005 the PreSCD II registry enrolled 10,612 MI survivors in 19 rehabilitation centres in Germany. Left ventricular function was determined in all patients one month or later after the index infarction, thus evaluating the risk for sudden cardiac death. All patients with a reduced ejection fraction of ≤40% plus a random sub-sample of the patients with preserved EF (n = 2058) were observed for at least 36 months for clinical events and mortality.

Commenting on the results, Professor Völler said: “Patients who survive myocardial infarction have an increased risk for sudden cardiac death. Randomised controlled trials like MADIT II and SCD-HeFT showed that patients with impaired left ventricular function are particularly protected against sudden cardiac death by an implantable defibrillator. All-cause mortality was reduced up to 31% by the ICD. However, in these trials the ICD was predominantly implanted several months after acute Mi. Other trials like DINAMIT and IRIS failed to demonstrate an ICD benefit if implanted early after myocardial infarction. International guidelines on anti-arrhythmic therapy reflect these results.

“The PreSCD II registry has confirmed the findings of the randomised clinical trials in a real life environment, where ICD implantation rates were lower than suggested by study results and guidelines. Noteworthy in this registry was an increasing reduction of mortality over time, depending on the time interval between index infarction and ICD implantation. However, when interpreting the data, it should be remembered that registry analyses do not in general have the confirmative power of a randomised controlled trial with causal connections.”

References

The PreSCD II registry was endorsed by the German Society of Cardiology (DGK) and the German Society for Prevention and Rehabilitation (DGPR), and supported by a grant from Boston Scientific Medizintechnik GmbH, Germany.

Results from the European CRT Survey

The European cardiac resynchronisation therapy (CRT) Survey is a joint initiative taken by the Heart Failure Association (HFA) and European Heart Rhythm Association (EHRA) of the European Society of Cardiology. Its primary objective is to describe current European practice and routines associated with the implantation of a CRT device with or without an ICD (implantable cardioverter defibrillator) capability in patients with heart failure.

The data collected from the survey provide useful information in CRT for heart failure on patient demographics and selection, clinical characteristics, diagnostic criteria, implantation routines and techniques, short-term outcomes, adverse experience, and assessment of adherence to guideline recommendations. These data should be useful for benchmarking individual patient management and national practice against wider experience. The data from randomised trials of CRT are limited and based largely on selected patients at high-volume centres with experienced operators. In contrast, the European CRT Survey describes current routine practice in CRT implantation based on a wide range of sampling.

Data were collected between 1st November 2008 and 30th June 2009 from 140 volunteer centres in 13 countries (Austria, Belgium, France, Germany, Ireland, Israel, Italy, Netherlands, Norway, Spain, Sweden, Switzerland, UK). Information was provided on consecutive patients successfully implanted with a CRT device with or without an ICD (CRT-P, CRT-D). All patients agreeing to participate will have a follow-up visit approximately one-year after CRT implantation.

Findings

The survey enrolled 2438 patients, with a mean age of 68 years (31% were 75 years or older). There are characteristic differences between those receiving CRT-P and CRT-D; the reasons are many, but it is clear that demographic and economic factors play a part. However, the Survey data show that younger patients, men and those with ischaemic aetiology are more likely to receive a CRT-D device.

The data also show that the cohort is remarkably similar to the cohorts recruited in randomised clinical trials (with a low proportion of women receiving CRT). However, patients in the Survey were older, and more frequently had mild symptoms. A substantial number had a narrow QRS complex (although a broadening is a typical finding in many trials) and more frequently had atrial fibrillation. However, in this real-world population, complication rates were similar to those reported in the randomised trials.

Says lead author Dr Nigussie Bogale from Stavanger University Hospital in Norway: “This European CRT Survey represents a reasonably large sample reflecting current European practice in the use of CRT devices in the management of patients with heart failure. Our findings show that many patients who do not strictly conform to current guideline recommendations frequently receive a CRT device. Clinicians, researchers and healthcare providers should find these data useful in designing strategies for patient management, trial design and resource allocation.”