Dr. Qaadri

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Heart Disease and Heart Failure

By Dr. Shafiq Qaadri, MD

What were some of the trial highlights at the European Society of Cardiology meeting?
The EUROPA trial asked a similar question as the HOPE study: do ACE inhibitors offer vascular protection, independent of their ability to lower blood pressure, in patients with atherosclerosis.

EUROPA assessed whether the ACE inhibitor perindopril reduced cardiovascular risk in a population with stable coronary heart disease and no apparent heart failure. 13,655 patients with coronary artery disease were treated with perindopril 8 mg once daily or matching placebo (n=6108). The primary endpoint was cardiovascular death, myocardial infarction, or cardiac arrest. There was a 20% relative risk reduction of the primary end point in perinodopril-treated patients.

How does the EUROPA trial compare to the HOPE study?
The patients in EUROPA and HOPE were both high-risk groups with no evidence of heart failure. Both trials demonstrated a significant reduction in myocardial infarction.

HOPE applies to a broader patient population that not only included coronary artery disease, as did EUROPA, but also peripheral or cerebrovascular disease, or diabetes mellitus with one other risk factor.
Ramipril 10 mg in HOPE appeared to have a more robust effect than perindopril 8 mg in EUROPA.

Ramipril reduced CV death, stroke, revascularization, and benefited diabetics, whereas perindopril did not.
Whether the difference in outcomes in the two studies is a reflection of more effective background medical therapy in EUROPA, a lower event rate, or a unique difference between the two ACEIs, is not known. What we do know is EUROPA confirms the unique vascular protective effects of ACEI first shown with ramipril in HOPE.

What is the ASA message?
For the high-risk cardiovascular patient, remember to offer Aspirin, a Statin, and an ACE Inhibitor, as this combination offers our patients robust cardiovascular risk reduction.

A number of patients are intolerant of ACEIs. How does the CHARM program address this?
The Angiotensin II receptor blockers (ARBs) are second-line therapy for congestive heart failure and reserved for the ACEI intolerant patients, and possibly for those unable to tolerate a beta-blocker. The CHARM Program consists of three separate placebo-controlled CHF trials (n=7601) with the ARB candesartan: 1) “CHARM Alternative” addresses the role of candesartan in ACEI intolerant patients; 2) “CHARM Preserved” questions the benefit of candesartan in patients with CHF but who have a normal ejection fraction; and 3) “CHARM Add On” asks the question--will candesartan provide an additional benefit when added to current CHF management, which includes both an ACEI and a beta-blocker?

Did this group of trials, the CHARM program, demonstrate that the ARB candesartan was superior to ACEI inhibitors for systolic heart failure?
CHARM does not compare an ACEI to candesartan and thus cannot answer that question. However, the ACEI captopril was recently compared with the ARB losartan in a meta-analysis of two CHF trials, ELITE II & OPTIMAAL.

Treatment with captopril was associated with a 10% relative risk reduction of all cause mortality as compared to losartan. Therefore, based on the meta-analysis, treating 55 CHF patients with captopril rather than losartan would result in one additional life saved.

Thus ACEIs remain the gold standard therapy with beta-blockers for heart failure. One of the three CHARM arms, the “CHARM-Alternative,” demonstrated that for patients with ACEI intolerance, candesartan had both a clinically and statistically significant reduction—23%--in the combined endpoint of hospital admissions for CHF and CV death.

The benefit seen with candesartan was driven mainly by the CHF component, rather than by a mortality reduction.

Does the ARB candesartan prevent death and MI when added to standard CHF treatment?
Standard therapy is maximal dose of ACEI and a beta blocker. The Val-Heft trial previously suggested that an ARB added in this situation actually increased mortality. In CHARM, there appeared to be a benefit in triple therapy with a 15% relative reduction in CHF admissions and CV deaths.

However, for those 64% of patients on a beta blocker, it is not possible to determine if the benefit of added candesartan was influenced by whether the patients were on target doses of ACEI or not.
Therefore, my practice of not using triple therapy will not change at this point in time, but I will keep an open mind for upcoming discussions with my colleagues, and more importantly, for the results of VALIANT.

With regard to the CHARM results, can the ARB candesartan be used in patients with diastolic dysfunction?
In diastolic dysfunction, the heart has preserved contractility—an ejection fraction greater than 40%--but the heart is “stiff.” This leads to trouble filling during diastole.

Diastolic dysfunction is most common in elderly females with hypertension and diabetes and may account for 30-40% of CHF hospital admissions.

The “CHARM Preserved” arm addressed the role of the ARB candesartan in diastolic dysfunction and the results were very disappointing and alarming. Despite candesartan reducing BP by 7/3 mm Hg, the combined endpoint of cardiovascular death and admissions for CHF remained unchanged.

Regardless, the majority of patients that qualified for “CHARM Preserved” should probably now receive an ACEI because these patients have comorbidities for which ACEI have been demonstrated to reduce mortality; for example, 60% of “CHARM Preserved” patients had angina, 44% had myocardial infarction, 37% coronary revascularization, 28% diabetes mellitus, and 18% left ventricular hypertrophy. Therefore, CHARM did not demonstrate any value of using the ARB candesartan in this population.

What is your final word about candesartan, and more broadly—ARBs-- for the management of heart failure by primary care physicians?
CHARM is a landmark study that suggests that the ARB candesartan is a reasonable choice for the ACEI intolerant patient with CHF and systolic dysfunction (an ejection fraction less than 40%).

However, candesartan did not reduce the combined endpoint of CHF and CV death in those patients with diastolic dysfunction, and thus should not be used for those patients. On the other, because of comorbidities, for the majority of these patients, an ACEI is the appropriate choice.

The jury on triple therapy for CHF, I believe, is still out, and there will be much debate in the cardiology community on this. I think the VALIANT trial of 15,000 patients, due in the fall, will provide the definitive answer.

Why were the results of CHARM so surprising to cardiologists?
What remains a mystery is the lack of benefit in high-risk patients with diastolic dysfunction. A large number of these patients had established coronary artery disease, and despite a sustained reduction in blood pressure, there was no reduction in cardiovascular events.

This reinforces the observations made in several trials--OPTIMAAL, IDNT, RENAAL and LIFE--that ARBs may not be the same as ACE inhibitors in terms of protection against myocardial infarction.

The ability of ACE inhibitors to augment bradykinin-dependent protective mechanisms has been suggested by some to be the key-differentiating factor between vascular protection offered by an ACE vs. an ARB, but ongoing research will elucidate this further.

What are the clinical implications of trials such as EUROPA for the primary care physician?
EUROPA emphasizes the fact that ACE inhibition should be used for vascular protection in patients with coronary atherosclerosis, independent of their blood pressure.

It is important to note that the EUROPA conclusions extend to patients with established CAD, and not to patients with cerebrovascular disease, diabetes, or peripheral vascular disease, a population that was studied in HOPE.

As such, in patients with established CAD, the primary care physician may use either perinodoril 8 mg per day or ramipril 10 mg per day; however, in high-risk diabetic patients, and patients with non-coronary atherosclerosis, ramipril 10 mg per day remains the standard treatment.

Dr. Shafiq Qaadri is a Toronto family physician and Continuing Medical Education lecturer. www.doctorQ.ca

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