Reports

Two very large studies, each likely to be a landmark in directing risk management, are nearing completion. The ONTARGET/TRANSCEND (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial and the parallel Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease) programme, conducted at centres in 40 countries, randomized more than 31,000 patients. The key question posed by the ONTARGET portion, with 25,620 patients, will be whether the angiotensin receptor blocker (ARB) telmisartan, the ACE inhibitor ramipril, or the combination is superior for preventing cardiovascular (CV) events in high-risk patients without elevated blood pressure (BP). Promising to be equally influential in guiding stroke prevention, the PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes) trial randomized more than 20,000 patients in a 2 x 2 factorial design to one of two antiplatelet treatments plus telmisartan or placebo. Both trials will be completed in the next few months.

“There have been a lot of surprises in randomized trials, which is why we need these types of head-to-head comparisons before drawing conclusions,” reported Dr. Marc A. Pfeffer, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.

Due to the fact that both ARBs and ACE inhibitors block the renin-angiotensin system (RAS), it has been widely assumed that the agents have very similar and perhaps interchangeable effects. Dr. Pfeffer presented a variety of data suggesting that this is not true, and that the results of ONTARGET are difficult to predict. In independent trials, ARBs and ACE inhibitors have not appeared to be interchangeable for such end points as myocardial infarction (MI) and stroke, and there are a number of reasons to predict that a combination of both will be superior to either alone.

Evaluating Benefits Independent of BP Reduction

In ONTARGET (the companion TRANSCEND study is randomizing ACE inhibitor-intolerant patients to telmisartan or placebo), the population is similar to that of the previous HOPE (Heart Outcomes Protection Evaluation) trial (N Engl J Med 2000;342:145-53). In HOPE, ramipril 10 mg produced a 22% reduction (P<0.001) in major CV events in high-risk patients without heart failure (HF) despite very modest reductions in BP. In ONTARGET, the largest clinical study to include an ARB that has ever been conducted, a similar population was enrolled and randomized to telmisartan 80 mg, ramipril 10 mg or a combination of both. Patients did not have hypertension (or had controlled hypertension) at entry, so relative benefits are expected to be independent of BP control. The composite primary end point is stroke, MI, CV death and hospitalization for HF. Secondary end points include rates of HF, revascularization procedures, new-onset diabetes, nephropathy, new-onset atrial fibrillation and left ventricular hypertrophy.

“This will greatly increase what we know about the relative strengths of these strategies for RAS inhibition,” maintained Dr. Pfeffer, who noted that ARBs and ACE inhibitors block the effects of elevated RAS by different mechanisms of action. For example, while ACE inhibitors block one of several enzymes responsible for angiotensin II production, ARBs block angiotensin II at its receptor sites, likely providing a more complete angiotensin inhibition, particularly at target tissue receptors. In addition, by blocking the AT1 receptor, more angiotensin II is available to stimulate AT2 receptors, which have been associated with antiproliferative activity.

Although ONTARGET has been characterized as an ARB-vs.-ACE inhibitor comparison, it is not clear whether this is appropriate. On the scale of a HOPE trial, ramipril is the only ACE inhibitor evaluated for BP-independent benefits in high-risk patients, while telmisartan has features that distinguish it from other ARBs. For example, the 24-hour half-life of telmisartan is more than double that of valsartan and candesartan, an important potential difference for consistent protection over each dosing period. In addition, it has been linked to improvements in glucose and lipid metabolism through actions on nuclear receptors not shared by other ARBs. Several single-centre comparisons have provided support for greater improvement in glucose metabolism on telmisartan than alternative ARBs. The applicability of results of ONTARGET to other agents in the ARB class is therefore likely to be controversial.

The same issue may be relevant for interpreting results of the PRoFESS study, a 2 x 2 factorial design trial comparing strategies for secondary prevention of stroke. Patients were randomized to extended-release dipyridamole plus ASA or to clopidogrel and randomized to telmisartan or placebo. This is the largest secondary stroke prevention trial ever conducted with approximately 5000 patients in each of the four arms (total study population of 20,233 patients). Both dipyridamole/ASA and clopidogrel have been found more effective than ASA for stroke prevention in the past, but this is the first direct comparison of these strategies. ARBs have been found more effective than other antihypertensive agents, such as calcium channel blockers, for secondary stroke prevention, but the long half-life of telmisartan is particularly attractive for preventing the large increase in stroke incidence associated with the early morning BP surge.

“The primary outcome of PRoFESS is prevention of recurrent stroke. Secondary outcomes include other vascular events, such as MI as well as new or worsening HF,” reported Dr. Philip Teal, Professor of Neurology, British Columbia Centre for Stroke and Cerebrovascular Diseases, Vancouver. He also noted that strategies will be compared for protection against new-onset diabetes, which has previously been associated with ARBs.

The Importance of Early Detection of Proteinuria

The value of a long-acting agent such as telmisartan in preventing complications in any vascular bed is the increasing evidence that they are interrelated. In an analysis of this phenomenon, Dr. George L. Bakris, Director, Hypertensive Diseases Center, University of Chicago, Illinois, presented data demonstrating that renal proteinuria is a very strong predictor of stroke and CV events in diabetics and that chronic kidney disease is associated with increased CV morbidity and mortality even in the absence of diabetes. He emphasized the importance of monitoring renal function in hypertensive patients for early detection of proteinuria and to include a treatment that reverses this risk when it occurs. In type 2 diabetic patients, a series of studies with ARBs have demonstrated that reductions in proteinuria at six months is a good predictor of CV outcomes as well as renal outcomes.

“Kidney disease is a silent killer. There are typically no clinical signs until more than 70% of renal function is lost. Yet a 50% reduction in kidney function doubles the risk of a CV risk relative to the general population,” Dr. Bakris told the audience. He suggested that there has been a recent evolution toward earlier recognition of renal impairment, particularly signs of microalbuminuria, because of clear evidence that preserving renal function is far more effective than treating renal impairments and preventing CV complications.

Other Lipid Subfractions

For other risks, such as hypercholesterolemia, the field is also moving quickly. According to Dr. Lawrence A. Leiter, Head, Division of Endocrinology and Metabolism, St. Michael’s Hospital, Toronto, Ontario, efforts are intensifying to build on risk reductions achieved with lowering LDL-C by looking at other lipid subfractions. While he acknowledged that the failure of the HDL-C-raising agent torcetrapib to improve outcome was a disappointment, he does not believe that it refutes the hypothesis that raising HDL-C is beneficial. He noted that a variety of strategies for raising HDL-C are in development, and more information is imminent.

Summary

Optimal care of patients at CV risk is in constant transition, but clinicians can expect an exceptional amount of new information over the short term. ONTARGET and PRoFESS have the potential to have an immediate impact on evidence-based practice for high-risk patients and secondary stroke prevention, respectively, while other innovations in the fields of nephrology and lipid management also appear to be imminent. These developments promise an evolution in routine care.

Based on the CCS/CCC-sanctioned session:

“Maximizing the Benefits of Prevention Strategies in Cardiovascular Disease.” Saturday, October 20, 18:00-21:00, Room 200C, Level 2.