First Report® Conference Coverage: American Heart Association, New Orleans, LA, November 8-12, 2008

Aliskiren Monotherapy Superior to Ramipril Monotherapy at 12 Weeks, Aliskiren-Based Therapy Noninferior to Ramipril-Based Therapy at 36 Weeks in Elderly Patients with Systolic Hypertension

New Orleans—In elderly patients with systolic hypertension, aliskiren monotherapy was noninferior to ramipril monotherapy at week 12, week 22, and week 36, and achieved a greater reduction in systolic blood pressure. Aliskiren was more successful than ramipril in achieving target blood pressure control, and a smaller percentage of patients treated with aliskiren-based therapy required add-on therapy with hydrochlorothiazide (HCTZ) and amlodipine. Both drugs were safe and well tolerated, with the exception of cough, which occurred in 30% of the ramipril-treated group but only 4% of the aliskiren-treated group.

Treatment for isolated systolic hypertension relies on blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), and, most recently, the first direct renin inhibitor, aliskiren. Although ACE inhibitors and ARBs are considered first-line treatment, more than two-thirds of patients require two or more drugs to achieve target blood pressure, explained Daniel Duprez, MD, of the University of Minnesota, Minneapolis. Dr. Duprez reported results of the AGELESS study, which was designed to compare the effects of aliskiren with those of ramipril on lowering systolic blood pressure in a group of elderly patients with systolic hypertension. The study was sponsored by Novartis Pharmaceutical Corp.

AGELESS was a 36-week, double-blind, parallel-group, active-controlled trial with 457 patients randomized to aliskiren and 444 to ramipril. At baseline, mean age of both groups was 72 years. Mean sitting systolic blood pressure (msSBP) was >140 mmHg and < 180 mmHg. About 50% of participants were female. Patients age 75 years or older comprised about one-third of the study population.

After a 4-week washout period, treatment was initiated with aliskiren 150 mg/day versus ramipril 5 mg/day. At 4 weeks, if msSBP was >140 mmHg, doses of both drugs were doubled. HCTZ 12.5 mg/day was added if msSBP was not controlled at 12 weeks, and the dose of HCTZ was doubled if needed at 16 weeks. If msSBP remained >140 mmHg at 22 weeks, amlodipine 5 mg/day was added; at 28 weeks, if msSBP remained >140 mmHg, the dose of amlodipine was doubled.

Aliskiren monotherapy was deemed noninferior to ramipril monotherapy for the primary end point (ie, change from baseline msSBP at week 12). In fact, at week 12, aliskiren achieved a reduction of -13.96 mmHg versus a reduction of -11.64 mmHg for ramipril. Aliskiren was superior to ramipril in lowering msSBP at week 12 and also at week 22, when HCTZ was added, Dr. Duprez said. At week 36, aliskiren achieved a mean reduction of –19.97 mmHg in msSBP versus a reduction of -18.05 mmHg for ramipril-based therapy. Aliskiren was noninferior to ramipril but not superior, Dr. Duprez added.

At week 12, 46.3% of the aliskiren group versus 39.3% of the ramipril group achieved blood pressure control (P = .03 for aliskiren vs ramipril). At week 22, blood pressure control was achieved in 69% versus 57.7%, respectively (P = .0005). At week 36, more patients treated with aliskiren-based therapy remained at goal.

Patients treated with ramipril required more add-on therapy, including HCTZ and amlodipine, than those treated with aliskiren, Dr. Duprez noted.

During the discussion following his presentation, Dr. Duprez was asked why maximal doses of aliskiren were allowed in the trial but only usual care doses of ramipril. He said the dose of ramipril 5 mg to 10 mg/day was based on the dose used in the HOPE trial.
________________________________________________________________

Very Elderly Experience Prolonged Survival and Enhanced Quality of Life Following Aortic Valve Surgery

New Orleans—The growing proportion of elderly patients in the United Sates highlights the need for geriatric studies to guide the management of cardiovascular disease. Two separate papers presented at the AHA meeting focused on an often-excluded group of patients. Both studies found that octogenarians can derive important benefits from aortic valve replacement surgery (AVR) and coronary artery bypass graft (CABG).

AVR With or Without CABG
Octogenarians have a favorable response to AVR procedures, according to a retrospective review of medical records for 8791 patients. Although the surgery posed an early upfront risk of death, most patients were alive at 6 years following surgery. In patients who underwent both AVR and CABG, survival was only slightly diminished.

“Survivorship following AVR is similar to that of the general population,” said Donald S. Likorsky, PhD, assistant professor, Dartmouth Institute for Health Policy and Clinical Practice, Dartmouth College, Lebanon, New Hampshire. Dr. Likorsky reported results of a study conducted by the Northern New England Cardiovascular Disease Study Group that included patients undergoing AVR in northern New England between 1989 and 2006.

The group was stratified according to age: <80 years, 80-84 years, and >85 years. Data were linked to the Social Security Administration dataset and adjusted for patient and disease characteristics. In-hospital mortality associated with AVR was 3.8% for <80 year olds, 6.9% for those aged 80-84, and 10.3% for those aged 85 and older. In-hospital mortality for patients who underwent AVR and CABG was 6.6%, 10.8%, and 9.2% for the respective age groups. Survival was longest among patients under age 80, regardless of whether they had AVR alone or AVR and CABG. Median survivorship was 11.5 years for AVR and 9.4 years for AVR plus CABG. Median survival was similar among other age groups (about 7 years) for AVR and for AVR plus CABG.

CABG in Octogenarians
Another retrospective review of 1062 patients 80 years or older who underwent isolated on-pump CABG between January 1989 and December 2001 showed that those who underwent the procedure experienced both increased survival rates and excellent patient perception of quality of life. Half of the group survived 6 years or more, and one quarter lived for 10 years.

This first large analysis of mortality rates among octogenarians found that CABG resulted in an operative mortality similar to that of the general population. Intermediate follow-up revealed an excellent perception of quality of life equal to that of an age-matched population, and late survival rivaled that of the general age-matched population, said Paul Kurlansky, MD, director of research, Florida Heart Research Institute, Miami, Florida.

Overall hospital mortality for the entire study period was 9.7%. Over time, in-hospital mortality decreased from 14.5% in 1989-1991 to 2.2% in 2001-2003, probably reflecting improved surgical technique, according to Dr. Kurlansky. Preoperative predictors of hospital mortality were date of surgery (P=.006), arrhythmia (P=.004), abnormal ejection fraction (P=.010), renal insufficiency (P=.001), and nonelective surgical urgency (P=.015). Intraoperative predictors were saphenous vein surgery (P=.030) and perfusion time (P=.011).

Quality of life assessment of physical and mental health using the Short Form-36 questionnaire showed no difference between 545 patients and published norms. Preoperative variables predicting late mortality included age at operation (P=.001), congestive heart failure (P=.034), peripheral vascular disease (P=.001), renal insufficiency (P=.001), stroke (P=.012), arrhythmia (P=.013) and prior myocardial infarction (P=.035). Renal insufficiency was the only significant postoperative variable for late mortality (P=.001).
___________________________________________________________________________________________________

Drug-Eluding Stents Superior to Bare-Metal Stents in Patients with Diabetes

New Orleans—In a real-world study of patients with type 2 diabetes mellitus undergoing percutaneous coronary intervention (PCI) with stenting, drug-eluting stents (DES) were superior to bare-metal stents (BMS), with reduced mortality, myocardial infarction (MI), and revascularization rates at 3 years of follow-up.

“DES achieves a clear reduction in the need for target vessel revascularization [TVR], and this is augmented by the fact that DES and BMS have similar safety in diabetic patients with similar characteristics,” said Laura Mauri, MD, Brigham and Women’s Hospital and Harvard Clinical Research Institute in Boston, Massachusetts.

About one third of angioplasties in the United States are performed on patients with diabetes. These patients have a higher prevalence of ischemic disease and a higher rate of restenosis, myocardial infarction (MI), and cardiac mortality periprocedurally and over the long term following PCI, Dr. Mauri explained.

The observational study was based on Mass-DAC Registry data on all adult Massachusetts residents with diabetes mellitus undergoing PCI with stenting between April 1, 2003, and September 30, 2004. Two groups were analyzed: those treated with DES (n=3341 patients) and those treated with BMS (n=1710 patients). Of DES-treated patients, 73% received sirolimus-eluting stents and 25% received paclitaxel-eluting stents only. The other 2% received both types of stent and were excluded from the analysis.

The two groups had differences in clinical and procedural baseline characteristics. Diabetic patients presenting for emergency procedures or with MI were more likely to receive BMS, whereas younger patients, those with hypertension or hyperlipidemia, and those with left anterior descending artery lesions were more likely to be treated with DES, Dr. Mauri explained. The BMS group had a slightly higher number of diseased vessels, but the number of vessels actually treated was higher in the DES group. To adjust for these differences and allow comparison between groups, propensity-score matching was done on 67 variables.

The study population included 5051 persons with diabetes treated with DES or BMS during the specified time period. Patients with diabetes were significantly more likely to receive DES than BMS: 66.1% versus 33.9%, respectively (P<.001). One third of the diabetic patients required insulin, she said. Based on a propensity-score–matched analysis of 1476 DES patients and 1476 BMS patients, risk-adjusted mortality, MI, and TVR rates at 3 years significantly favored DES (P=.02). Risk-adjusted mortality was 17.5% versus 20.7%, for an absolute reduction of 3.2% (P=.02). MI rates were 13.8% versus 16.9%, for an absolute reduction of 3.1% (P=.02). The rates of TVR were 18.4% versus 23.7%, an absolute reduction of 5.4%, which was highly significant (P=.001).

Looking at effects over time with the 2 types of stents, no difference was observed in early versus late hazards. The separation of curves remained similar over follow-up.

When Dr. Mauri was asked whether she would recommend DES in all diabetic patients undergoing stenting, she said the decision between DES and BMS should incorporate individual patient factors.

No Hazard with DES
“One of major drawbacks of PCI in patients with diabetes is the need to perform repeat revascularization. DES offer a theoretical improved option, but the concern has been that they are not as safe as BMS in these patients with very aggressive coronary disease. The finding that DES pose no hazard is surprising,” said formal discussant David O. Williams, MD, of Rhode Island Hospital in Providence.

The study deserves credit for being based on a robust data source that allowed evaluation of PCI in an unrestricted environment, Dr. Williams continued. Potential weaknesses of the study are its observational design and use of a propensity analysis to correct for substantial differences in the baseline characteristics of the two groups. “This is the best approach for this type of investigation, but we don’t know if it corrects for all imbalances,” he said.

“It is appropriate to conclude that DES are superior to BMS in reducing the need for TVR in patients with diabetes. Whether there is an actual benefit, as found in this observational study, is a provocative finding that deserves further study. Whenever possible, DES should be used over BMS in patients with diabetes. The selection of a stent will also depend on the patient’s ability to take antiplatelet therapy over time,” Dr. Williams commented.
____________________________________________________________________________________________________

Medicare Beneficiaries with Heart Failure See More Providers than Typical Beneficiaries

New Orleans—Medicare beneficiaries diagnosed with heart failure (HF) see 2 to 3 times as many separate providers as typical Medicare beneficiaries, according to the first large study to quantitate provider visits for HF patients. The overwhelming majority of provider visits were for comorbidities of HF.

“We think this is important because when patients see an increasing number of providers, that means they will be prescribed an increasing number of drugs, which increases the risk of drugrelated adverse events. If a patient takes more than 4 different medications, the risk of adverse drug reactions is greater than 50%. An average ambulatory patient age 65 or older takes 5 or more different medications per week,” said Robert L. Page II, PharmD, of the University of Colorado in Denver. Dr. Page presented the study results at a poster session during the AHA meeting.

To illustrate the potential magnitude of the problem, Dr. Page explained that three quarters of HF patients are age 65 or older. In 2005, Medicare beneficiaries with HF accounted for 37% of all Medicare spending and nearly 50% of all hospital inpatient costs. 

The study was based on a 5% sample from a 2005 CMS database for the entire United States and included 34 million people. About 6 million people had HF. Medicare claims do not capture New York Heart Association (NYHA) class, Dr. Page explained. One of the coauthors of the study, Christopher Hogan, PhD, from Direct Research, LLC, in Vienna, Virginia, devised a novel method of stratification by disease severity based on utilization data and predefined categories from Medicare’s Chronic Care Improvement Program. Physicians were identified based on their unique physician identification number.

Three different cohorts were defined: mild HF, moderate HF, and severe HF. While a typical Medicare beneficiary saw 7.9 different providers in the year 2005, patients with severe HF saw 23.1 different providers, those with moderate HF saw 18.6 different providers, and those with mild HF saw 15.9 different providers. These provider visits take into account ambulatory visits, emergency department visits, and hospitalizations, Dr. Page explained. Of these, the mean number of physicians ordering care was 4.7 for typical Medicare beneficiaries, 11.2 for those with severe HF, 9.6 for those with moderate HF, and 8.3 for those with mild HF.

Beneficiaries with HF had an average of 10.3 outpatient visits with at least 2 prior HF hospitalizations within the index period. Ten percent of outpatient visits were specifically for HF in patients categorized as mild HF, while 20% of outpatient visits were specific to HF in the moderate and severe HF groups. Depending on the severity of HF, 80% to 90% of provider visits were for comorbidities. The top 4 comorbidities, based on Medicare codes, were arrhythmias, diabetes mellitus, chronic obstructive pulmonary disease, and vascular disease.

“These data showing that a large number of providers are ordering and providing care highlight the importance of developing systems and processes of coordinated care for HF patients,” Dr. Page said. 

Medicare’s promotion of separate disease-state management programs, or “silos,” is a contributor to the lack of coordinated care, according to Dr. Page. “We have to stop looking at diseases as silos. We need comprehensive care clinics or programs and improved communication between specialists and primary care physicians, and we need coordination that includes pharmacists,” he continued. He cited the VA system as an excellent example of coordinated care, and said that electronic medical records would help identify redundancies.
________________________________________________________________________________________________________

Prasugrel Reduced Ischemic Events Compared with Clopidogrel in TRITON TIMI-38

New Orleans—Regardless of the geographic region in which patients reside, treatment with prasugrel achieved consistent reductions in ischemic events compared with clopidogrel in patients with moderate- to high-risk acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) in the multinational TRITON TIMI-38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction). Prasugrel was also associated with increases in major bleeding versus clopidogrel across the 5 geographic regions. The regional analysis of TRITON TIMI-38 was presented by Christian T. Ruff, MD, Brigham and Women’s Hospital, Boston, Massachusetts, at an oral session during the AHA meeting.

These results mirrored the overall result of TRITON TIMI-38. “More intensive dual antiplatelet therapy appears to be beneficial regardless of differences in regional patient populations and practice patterns,” Dr. Ruff stated.

The study population included 13,608 patients with moderate- to high-risk ACS scheduled for PCI who were randomized to aspirin plus prasugrel or aspirin plus clopidogrel for 6 to 15 months without regard to geographic region. The regional analysis included North America (32% of patients), South America (4% of patients), Western Europe (26% of patients), Eastern Europe (24% of patients), and Africa/Asia/Pacific/Middle East (14% of patients).

The main results of TRITON TIMI 38, reported in the New England Journal of Medicine in 2007, showed that prasugrel achieved a 19% relative risk reduction in cardiovascular death/non fatal myocardial infarction (MI), or nonfatal stroke, which was significant (P<.001). Major bleeding was observed in 2.4% of prasugrel-treated patients versus 1.8% of those receiving clopidogrel (hazard ratio, 1.32, 95% confidence interval, 1.03-1.68; P=.03). Life-threatening bleeding was increased in the prasugrel group: 1.4% versus 0.9% (P=.01). Nonfatal bleeding rates were 1.1% versus 0.9%, respectively (not significantly different); and fatal bleeding rates were 0.4% versus 0.1%, respectively (P=.002). Overall mortality was not significantly different between treatment groups.

Clinical characteristics of patients differed broadly among regions, including age, comorbidities, ACS presentation, stent types, and adjunctive medications. Procedural characteristics also varied by geographical region, with the widest variations in use of drug eluting stents (from 8% in South America to 88% in North America) and glycoprotein IIb/IIIa inhibitors (from 22% in South America to 75% in North America).

Despite these regional differences, improvement in efficacy and excess bleeding were consistent with prasugrel. In each region of the world, stent thrombosis was substantially reduced with prasugrel, and net clinical benefit (death/MI/stroke/non-CABG major bleed) was also improved with prasugrel. Clinical benefit ranged from a relative risk reduction of 13% to 24% across the 5 regions. Excess bleeding with prasugrel ranged from a relative risk increase of 16% to 76% across the 5 regions.