Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

Canadian Cardiovascular Congress 2006

Vancouver, British Columbia / October 21-25, 2006

Assessing individual patient risk in order to offer timely and appropriate risk-reducing interventions is paramount to the successful management of patients with cardiovascular disease (CVD). This is all the more true for the highest-risk patients who derive the greatest benefit from proven strategies.

The Role of eGFR

Among risk factors less likely to be assessed but which nevertheless significantly influence outcomes is the estimated glomerular filtration rate (eGFR). As discussed by Dr. Marc Pfeffer, Professor of Medicine, Harvard Medical School, Boston, Massachusetts, the eGFR is a major predictor of CVD events even in patients without chronic kidney disease.

In VALIANT (Valsartan in Acute Myocardial Infarction Trial), the hazard ratio for a major CV event was 1.7 for those with an eGFR <45 mL/min/1.73 m2 compared with 0.9 for those with an eGFR of ³75 mL/min/1.73 m2. In this trial, the influence of eGFR on adverse CV outcomes was independent of diabetes, although a low eGFR impaired prognosis to a greater extent in patients with diabetes. Patients who were diagnosed with diabetes during the trial experienced similar adverse outcomes as those who had been diagnosed prior to entry, “even though newly diagnosed patients were younger and had less of a history of coronary artery disease (CAD),” observed Dr. Pfeffer.

Higher-risk Patients = Less Treatment: The Paradox

As demonstrated in VALIANT and several other studies, the lower the patient’s eGFR, the less likely they are to receive proven therapies. This may be explained, Dr. Pfeffer suggested, by concerns that patients with compromised renal function do not tolerate various therapies well, or that they are too fragile and susceptible to side effects. But as many analyses indicate, proven therapies produce greater absolute risk reductions in higher-risk patients such as those with lower eGFR—“all the more reason we should try to treat them with proven agents,” he noted.

In VALIANT, over 14,000 acute myocardial infarction (AMI) patients receiving conventional therapy were randomized to the angiotensin II receptor blocker (ARB) valsartan 160 mg b.i.d., captopril 50 mg t.i.d. or lower-dose combination valsartan 80 mg b.i.d. plus captopril 50 mg t.i.d. A four-step titration process was used with both agents in order to bring as many patients as possible to their highest possible tolerable dose.

Findings showed that hospitalization rates for angina, stroke and the need for revascularization rates were comparable across the three treatment groups. Regarding individual atherosclerotic events over the study, “there was no case where the ARB wasn’t comparable to the ACE inhibitor,” Dr. Pfeffer commented. Results also demonstrated that the ARB was at least as protective against atherosclerotic events (including MI) as a proven ACE inhibitor given at a proven dose in AMI patients (Figure 1).

Figure 1. MIs and Other Atherosclerotic Events in VALIANT

<doc33|centre>

Dr. Pfeffer told the audience, “In VALIANT, we really took the high road and said, ‘these are patients who we know an ACE inhibitor would work in, so let’s go against a proven ACE inhibitor at a proven dose.’ When it was all over, we were very confident that we did use the ACE inhibitor optimally and the ARB arm was superimposable over the ACE inhibitor arm”—thereby proving the trial’s non-inferiority hypothesis. This, he added, led to the ARB’s indication, alone among its class, as a proven strategy to lower MI in high-risk patients.

Identifying Patients at Highest Risk for Major Events

Dr. Scott Solomon, Associate Professor of Medicine, Harvard Medical School, reminded delegates that 40% of study patients experienced a major adverse CV event over the course of the trial. Recent analyses indicate that 11% of VALIANT patients had a second MI after their index event, “and if a patient had a second event, 53% of them died during the trial vs. 15% of patients who did not have a recurrent event,” Dr. Solomon reported. “Age was the most important predictor of having a second MI,” he added, but diabetes, smoking and hypertension emerged as important risk factors for a second MI as well.

In contrast, no predictors of sudden death could be identified, although the risk of sudden death was about 2% per month in the first month after the index MI in patients with an ejection fraction (EF) <30%. Another high-risk group identified in the VALIANT analysis were those who had an admission for heart failure. Dr. Solomon remarked, “If we take a diabetic patient with an EF of 40%, that patient will have the same risk of dying or developing heart failure as a non-diabetic with an EF of about 25%.”

Diabetes and the RAS Connection

It is well established that patients with diabetes are at high risk for CVD events. Although hypothesized that prevention of diabetes is likely to reduce CVD risk, this has yet to be adequately demonstrated by trials large enough to offer confirmatory evidence. To that end, investigators have designed the NAVIGATOR study to determine whether valsartan with or without nateglinide can prevent both diabetes and CVD events in patients with impaired glucose tolerance (IGT). As noted by Dr. Lawrence Leiter, Professor of Medicine and Nutritional Sciences, University of Toronto,Ontario, evidence suggests that agents that target the renin-angiotensin system (RAS) may prevent new-onset diabetes, while nateglinide ameliorates early defects in IGT that are predictive of progression to diabetes.

Novel Class of Agents

It is now well-established that hypertension is among the most important risk factors for CVD, especially for stroke. Consequently, getting patients to blood pressure (BP) targets is critical for optimal outcomes. Dr. Richard Lewanczuk, Professor of Medicine and Physiology, University of Alberta, Edmonton, stated that when the first of a new class of direct renin inhibitors, aliskiren, becomes available, it will immediately expand the armamentarium to six different classes of antihypertensives, offering patients more combinations to get to treatment goals.

Unlike ACE inhibitors and ARBs, aliskiren blocks the RAS at its rate-limiting step when angiotensinogen is converted to angiotensin I. As Dr. Lewanczuk indicated, it is becoming more widely appreciated that stimulation of the renin receptor is associated with adverse CV effects and as such, an agent that is antagonistic toward this process may demonstrate benefit over and above those associated with BP reduction. Pharmacokinetic studies indicate that it has a long half-life of approximately 40 hours allowing for once-daily dosing. It is mostly eliminated via biliary excretion as unmetabolized drug, thereby reducing the likelihood of significant drug-drug interactions.

As monotherapy, aliskiren at a dose of 150 and 300 mg produces significant reductions in diastolic and systolic BP equivalent to other antihypertensive agents, affecting BP control quickly within the first or second week. There is also no rebound hypertension on dose withdrawal, and the drug is well tolerated with a placebo-like safety profile. When used with either an ACE inhibitor or a calcium channel blocker, it offsets both cough and peripheral edema. The combination of aliskiren plus other antihypertensive agents has also consistently been shown to produce greater reductions in BP than either drug alone.