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.

55th Annual Scientific Sessions of The American College of Cardiology (ACC)

Atlanta, Georgia / March 11-14, 2006

Recent progress toward defining better approaches to the control of both dyslipidemias and hypertension has been reinforced by new data presented at the 2006 scientific sessions of the American College of Cardiology. In high-risk patients, there remains little doubt that reducing LDL-C to levels <2.0 mmol/L provides an incremental reduction in cardiovascular (CV) events relative to less rigorous control and the additional benefit of even lower levels is now being evaluated. In hypertension, we have observed compelling evidence that drug classes are not necessarily interchangeable for CV risk reduction even with the same blood pressure (BP) control. Since many high-risk patients with one of these risk factors have the other, the challenge is employing new information to treat both risk factors simultaneously to recommended targets.

Supplementary Evidence for Lower LDL-C Goals

There is now overwhelming support for the premise that “lower is better” in regard to LDL-C for patients with established coronary heart disease (CHD). The data from a series of recent studies such as PROVE-IT/TIMI-22 (NEJM 2004;350(15):1495-1504) and TNT (Treating to New Targets)(NEJM 2005;352(14):1425-35), both of which compared a target LDL-C of <2.5 mmol/L to a target of <2.0 mmol/L, have confirmed that the risk of CV events is reduced significantly at the lowest LDL-C levels. The mechanistic support for these clinical findings was shown by REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering), in which intravascular ultrasound was used and demonstrated that treating patients with atorvastatin 80 mg to reach an LDL-C of <2.0 mmol/L provided protection against growth of atherosclerosis (JAMA 2004;291(9):1071-80).

A series of recently reported TNT substudies, which compared atorvastatin 80 mg to the 10-mg dose in patients with stable CHD, have confirmed the relative benefits of the higher dose while maintaining the absence of significant safety issues. In TNT, the 80-mg dose reduced the average LDL-C to approximately 2.0 mmol/L vs. approximately 2.6 mmol/L with the 10-mg dose. The greater reduction in LDL-C produced a 22% relative risk reduction of major CV events (P=0.002). When specific risk groups were evaluated separately, all patients on the more aggressive lipid lowering moved in a favourable direction relative to risk reduction of CV events. Some groups benefited more than the general study population: in diabetic patients, the relative reduction of major CV events in TNT reached 25% (P=0.026) for the more aggressive vs. the less aggressive lipid-lowering treatment; in patients with metabolic syndrome, the relative reduction in CV events reached 29% (P<0.0001).

In Pursuit of Safety and Lower Lipid Levels

The overall safety data from TNT did not reveal any significant increase in adverse events among those who received the more aggressive lipid lowering. When an even more detailed analysis was conducted to study safety at the very lowest levels of LDL-C by dividing LDL-C into quintiles, there was still no signal of a significant increase in risk. In fact, no pattern of risk for adverse events could be discerned between the quintiles, even though there was a stepwise reduction in major CV events for each lower level of LDL-C.

The data from the recent lipid trials follows a trajectory toward more aggressive lipid lowering that began more than 10 years ago with 4S (Scandinavian Simvastatin Survival Study)(Lancet 1994:344(8934):1383-9). To date, each incremental reduction in LDL-C evaluated has produced a further incremental reduction in CV risk. While the clinical benefit of reducing LDL-C to <2.0 mmol/L in patients who have not yet progressed to CHD or a CHD equivalent has not yet been shown, testing of even more aggressive lipid lowering than that achieved in PROVE-IT and TNT is being considered in high-risk patients. If data derived from lipid levels in primitive hunter-gatherer populations is representative of physiologic levels of LDL-C, the optimal target may be as low as 1.0 mmol/L.

Seeking Optimal Hypertension Treatment Strategies

New trial data in hypertension have also provided new guidance about the optimal approach to control of this CV risk factor. Until recently, many treatment guidelines recommended ß-blockers or diuretics as first-line pharmacologic therapy in all patients with hypertension. While many guidelines now allow that other classes of BP-lowering agents may be preferable in selected patients, there is now a second study to show improved CV risk reduction with one class of agents relative to another at similar BP control. The first of these studies, published over three years ago, was the LIFE trial (Lancet 2002;359(9311):995-1003), which studied the angiotensin receptor blocker (ARB) losartan and the ß-blocker atenolol. It associated the ARB with a significant 13% reduction (P=0.02) in a composite end point of CV events.

The more recent of these studies was the BP-lowering arm of the ASCOT study (ASCOT-BPLA Anglo- Scandinavian Cardiac Outcomes Trial - Blood Pressure Lowering Arm) (Lancet 2005;366(9489):895-906), which compared an amlodipine-based treatment regimen with an atenolol-based regimen. Although BP control was slightly better in the calcium channel blocker (CCB) arm, it did not appear to account for the greater degree of CV risk reduction. In fact, the ASCOT-BPLA trial was stopped early on the data safety monitoring board recommendation because of the advantage of the CCB arm for reducing overall mortality.

In the ASCOT-BPLA trial, 19,257 hypertensive patients were randomized to the CCB or the ß-blocker. The ACE inhibitor perindopril was added as a second-line agent to the CCB arm and the diuretic bendroflumethiazide was added to the ß-blocker arm if needed to achieve BP goals. The 10% reduction in the prespecified primary end point of nonfatal myocardial infarction (MI) and fatal CHD in the ASCOT-BPLA trial fell short of significance because early termination reduced the anticipated accrual of clinical events; however, there was a statistically significant 11% reduction in all-cause mortality, a 24% reduction in CV mortality and a 16% reduction in the composite end point of CV death, MI or stroke for patients randomized to the CCB arm vs. the ß-blocker arm.

The ASCOT-LLA Conundrum

One of the issues raised by the ASCOT trials program, which also included a lipid-lowering arm, called ASCOT-LLA (Lipid Lowering Arm) (Lancet 2003;361(9364):1149-58), is whether there is an interaction between risk reduction strategies. In ASCOT-LLA, 10,305 of the hypertensive patients who participated in ASCOT-BPLA were randomized to receive atorvastatin 10 mg or placebo. That study was also stopped early by the data safety monitoring committee because a large mortality advantage in the statin arm that rendered further blinded analysis unethical. When a prespecified analysis was conducted to evaluate the two treatments for an interaction, the data suggested that patients in the amlodipine arm derived greater benefit from the statin than patients in the ß-blocker arm. Overall, it has been reported that the risk reductions of CHD and stroke exceeded 50% when hypertensive patients received both amlodipine and atorvastatin.

Compliance Key to Achieving Treatment Goals

The progress in better defining the treatment targets in dyslipidemia and hypertension as well as the optimal therapies to reach those targets has been important, but these will offer no protection to patients who are not compliant with therapy. The proportion of patients with either hypertension or hypercholesterolemia who are on treatment and at goal remains low in this country and elsewhere. It is even lower for those patients with both hypertension and hypercholesterolemia. While this may be due in part to physician failure to provide patients with adequately aggressive treatments, there are also problems with compliance. This problem may be exacerbated in patients with two or more risk factors requiring multiple medications. There are data to suggest that strategies such as simplifying regimens with pills that can be taken oncedaily or employing combination drug regimens to reduce pill counts may be effective in enlisting greater adherence.

Determining the Importance of Raising HDL-C

It has been suggested that the LDL-C story of CV risk reduction is nearing completion. Although the limit of LDL-C lowering at which point there is no further benefit has yet to be defined, it is clear that lower is better within the context of the potency of current therapies. However, not all CV risk can be explained by elevated lipids or hypertension. One target that is expected to become increasingly important in the future is raising HDL-C. Although HDL-C has long been recognized as an independent risk factor, new therapies reaching late stages of development may better characterize the importance of HDL-C much the way that statins were instrumental in characterizing the importance of LDL-C. Specifically, trials with such experimental agents as CETP inhibitors may serve both to underline the importance of HDL-C and to simultaneously validate the clinical efficacy of these therapies.

Summary

Although our understanding of optimal treatment for modifiable risk factors continues to evolve, it is important to recognize the enormous opportunities to reduce CV events by applying those treatments already associated with benefit. In high-risk patients, aggressive lipid-lowering should be standard of care on the premise that lower is better. In hypertensive patients, there is now clear evidence that antihypertensive drug classes are not interchangeable. In patients with both dyslipidemia and hypertension, the advantage of statins and newer antihypertensive agents is that they provide at least additive risk protection in the context of excellent tolerability. Both are attributes that should increase the likelihood of reaching treatment goals.