Biomarkers, Atherosclerosis and Cardiovascular Events

Abstract

The 57th Annual Scientific Session of the American College of Cardiology was held in Chicago (IL, USA) between 29 March and 1 April 2008. It was attended by nearly 30,000 participants from around the world. The conference was highlighted by the presentation of 13 late-breaking clinical trials and 13 late-breaking abstracts.

Established biomarkers fail to predict atherosclerosis & cardiovascular events

The causal relationship between LDL concentration atherosclerosis and atherosclerotic cardiovascular events has prompted reliance of LDL-cholesterol as a surrogate marker to establish efficacy of therapeutic interventions, even in the absence of evidence from randomized, double-blind, controlled clinical trials. Similarly, elevated blood pressure is a major risk factor for stroke, and it has been assumed that blood pressure lowering will reduce strokes and cardiovascular events. Unfortunately, the surrogate marker approach was challenged by the outcomes of some of these randomized clinical trials.

Work presented at the American College of Cardiology 57th Annual Scientific Session showed that some of the biomarker changes that are thought to reduce atherosclerosis burden and prevent cardiovascular events may not necessarily provide the signal that has been conventionally assumed for that surrogate marker. It was also demonstrated that the treatment of high blood pressure with different classes of antihypertensive therapies can yield striking differences in cardiovascular outcomes, despite similar reductions in blood pressure.

LDL-cholesterol, cholesterol absorption inhibition & atherosclerosis

LDL-cholesterol levels are incrementally associated with increased carotid artery intima media thickness (CIMT), coronary atherosclerosis and cardiovascular events. The Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial was a randomized, double-blind trial that compared the effects of daily therapy with 80 mg simvastatin either with placebo or 10 mg ezetimibe on 24-month changes in mean CIMT among 720 patients with familial hypercholesterolemia [1]. Ezetimibe, a cholesterol absorption inhibitor, reduced LDL-cholesterol by 16.5% versus placebo (mean ± standard deviation [SD]: 141.3 ± 52.6 mg/dl [3.65 ± 1.36 mmol/l] vs 192.7 ± 60.3 [4.98 ± 1.56 mmol/l]; p < 0.01) and C-reactive protein by 25.7% (p < 0.01). The primary outcome, mean ± standard error [SE] change in CIMT was not different between the treatment groups (p = 0.29). From a drug-development viewpoint, the unanticipated outcome in ENHANCE has caused profound consternation concerning regulatory approval of novel cholesterol-lowering agents based on the long-standing doctrine that over 15% reduction in LDL-cholesterol was an acceptable standard for a new cholesterol-lowering agent prior to demonstrable benefits on atherosclerosis and cardiovascular events. Yet ENHANCE has scientific limitations that warrant discussion before LDL-cholesterol is abandoned as a reliable surrogate of atherosclerosis and cardiovascular events. First, this was a 24-month trial in which 80% of the patients had been previously treated with a statin. It is known that statin therapy changes the composition of the atherosclerotic plaque leading to more fibrous, denser and less vulnerable lesions. In ENHANCE, baseline CIMT was 0.695 mm compared with 0.925 mm in the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) study performed 6 years earlier [2]. Second, the comparison group (simvastatin 80 mg daily) demonstrated no change in CIMT from baseline to 24 months (0.70 ± 0.13 mm vs 0.70 ± 0.14 mm). Since the study was designed to include sufficient study participants to account for a difference of 0.05 mm in CIMT, the trial was certainly underpowered as the comparison group did not change as anticipated.

Glucose-lowering strategies: effects of an insulin sensitizer versus an insulin secretagogue on atherosclerosis

With the controversy concerning the potential increased risk of cardiovascular events among Type 2 diabetes patients treated with rosiglitazone, two coronary atherosclerosis imaging trials with the thiazolidinediones, pioglitazone and rosiglitazone, provided incremental information concerning the differential effects of these therapies on vascular risk. The Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation (PERISCOPE) trial was designed to compare the effects of 18 months of treatment with pioglitzone, an insulin sensitizer, versus the sulfonylurea glimepiride, an insulin secretagogue, on the progression of coronary atherosclerosis in 543 Type 2 diabetes patients [3]. The primary outcome measure was change in percentage atheroma volume (PAV), as quantified by intravascular ultrasonography (IVUS). At study completion, 360 patients (66%) had repeat coronary IVUS examinations. In this trial, PAV increased by 0.73% (95% confidence interval [CI]: 0.33–1.12) in the glimepiride group and it decreased by 0.16% (95% CI: -0.57 to 0.25) with pioglitazone (p = 0.002). There were no differences in a composite of cardiovascular events, which included 40 heart failure events (14.8%) with pioglitazone and 41 events (15.0%) with glimepiride. However, bone fractures were more common amongst pioglitazone-treated patients (3.0 vs 0.0% with glimepiride). PERISCOPE should be considered a confirmatory trial for the anti-atherosclerotic effects of pioglitzone that were previously demonstrated in the Carotid Intimal-medial Thickness In Atherosclerosis Using Pioglitazone (CHICAGO) trial [4] and the secondary cardiovascular events observed in Prospective Pioglitazone Clinical Trial In Macrovascular Events (PROactive) [5]. In another thiazolidinedione trial employing coronary IVUS, 12 months of treatment with rosiglitazone in the Vein-Coronary Atherosclerosis and Rosiglitazone After Bypass Surgery (VICTORY) study was compared with placebo in preventing coronary atherosclerosis progression after coronary artery bypass grafting in 196 Type 2 diabetes patients. In contrast to the favorable effects of pioglitazone on native atherosclerosis, short-term treatment with rosiglitazone did not improve coronary atherosclerosis assessed by angiography or IVUS [6].

Endocannabinoid type 1 receptor antagonism & atherosclerosis

The Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant – The Intravascular Ultrasound Study (STRADIVARIUS) examined the effects of the selective endocannabinoid type 1 receptor antagonist rimonobant 20 mg daily compared with placebo on coronary progression in centrally obese patients with the metabolic syndrome [7]. Rimonobant patients had larger reductions in bodyweight (p < 0.001), waist circumference (p < 0.001) and metabolic parameters. After 18 months of therapy, there were no differences in the primary outcome measure, PAV (p = 0.22); however, total atheroma volume was reduced in the rimonobant group by 2.2 mm³ (95% CI: -4.09 to -0.24) compared with an increase of 0.88 mm³ (95% CI: -1.03 to 2.79) in the placebo group (p = 0.03). Psychiatric adverse reports (primarily anxiety and depression) were more common with rimonobant therapy (43.4 vs 28.4%; p < 0.001). It is uncertain as to the impact of this trial since there were no treatment differences in the primary outcome, and insufficient numbers of patients to examine the risks and benefits of this novel weight loss and metabolic agent.

High blood pressure

Meta-analyses of blood pressure treatment in patients over 80 years of age indicate a reduction in stroke that is offset by an increase in all-cause mortality [8]. These conflicting results were reflected in the pilot study for the Hypertension in the Very Elderly Trial (HYVET). The main trial was designed to resolve the risks and benefits of antihypertensive therapy in patients aged 80 years or older [9]. In this trial, 3845 patients with systolic blood pressure of over 160 mmHg were randomized to receive therapy with a diuretic (long-acting indapamide 1.5 mg) or placebo. The angiotensin-converting enzyme (ACE) inhibitor, perindopril (2 or 4 mg) or matching placebo were added in order to reduce the blood pressure to the target of 150/80 mmHg. At 2 years, the average blood pressure was 15.0/6.1 mmHg lower in the active treatment group than the placebo group. In the intention-to-treat analysis, active therapy was associated with a 30% reduction in the risk of fatal or nonfatal stroke (95% CI: -1 to 51; p = 0.06), a 39% reduction in fatal stroke (95% CI: 1–62; p = 0.05), a 21% reduction in the risk of all-cause mortality (95% CI: 4–35; p = 0.02) and a 64% reduction in the risk of heart failure (95% CI: 42–78; p < 0.001). In the per-protocol analyses, active treatment versus placebo treatment reduced the risk of stroke by 34% (95% CI: 5–54; p = 0.03) and risk of death from any cause by 28% (95% CI: 12–41; p = 0.001). HYVET provides clear evidence for hypertension treatment in individuals 80 years or older.

The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial investigated whether equivalent blood pressure lowering with an ACE inhibitor and diuretic (benazapril 20–40 mg, hydrochlorothiazide 12.5–25 mg and Amlodipine 5–10 mg) was different than combining an ACE inhibitor with calcium channel blocker. This trial included 11,462 hypertensive patients (systolic blood pressure > 160 mmHg or receiving antihypertensive therapy) and evidence of cardiovascular or renal disease or target organ damage [10]. Systolic blood pressure was 0.7 mmHg lower in the ACE inhibitor plus calcium channel blocker than the ACE inhibitor plus diuretic arm (129.3 vs 130 mmHg). After 30 months, the trial was terminated early due to 20% reductions in cardiovascular morbidity/mortality (p = 0.0002). This trial will inevitably change the stepped care approach to the treatment of hypertension that has been espoused by the Joint National Committee on Hypertension.

On-Target investigated whether the mechanism of renin-angiotensin system with an ACE inhibitor (ramipril 10 mg daily), angiotensin Type 1 receptor blocker (ARB; telmisartan 80 mg daily) or the combination of an ACE inhibitor plus ARB was accompanied by differences in cardiovascular death (myocardial infarction or stroke) or hospitalization for heart failure among 25,620 patients with vascular disease or diabetes with end-organ damage [11]. At 6 weeks, blood pressure was reduced by an average of 0.9/0.6 mmHg (7.4/5.0 vs 6.4/4.3 mmHg) more in the telmisartan group than the ramipril group. After 56 months, there were no differences in the primary outcome (16.5% in the ramipril group and 16.7% in the telmisartan group; relative risk: 1.01; 95% CI: 0.94–1.09). The telmisartan group had less cough and angioedemia, but more reports of hypotensive symptoms. Combination therapy was accompanied by a larger 6-week reduction in mean blood pressure (9.8/6.3 mmHg); however, there were no differences in 16.3% (relative risk: 0.99; 95% CI: 0.92–1.07) compared with the ramipril group. Furthermore, there was an increase in hypotensive episodes (4.8 vs 1.7%; p < 0.001), syncope (0.3 vs 0.2%; p = 0.03) and renal dysfunction (13.5 vs 10.2%; p < 0.001). This trial failed to establish the widely held concept that a lower blood pressure is accompanied by fewer cardiovascular events.

Home defibrillator

In the Home Automated External Defibrillator Trial (HAT) trial, 7001 patients with prior anterior wall myocardial infarction who were not candidates for an implantable cardioverter-defibrillator were randomized to one of two directed responses to sudden cardiac arrest in the home [12]. Eligible patients had spouses or companions that were able to call emergency medical services, perform cardiopulmonary resuscitation (CPR) and use an automated external defibrillator (AED). Randomization was made to either to use the AED followed by a call to emergency medical services and perform CPR or control therapy (call to emergency medical services and performing CPR). After a median follow-up of 37.3 months, there were no differences in mortality (222 of 3495 [6.4%] in the AED group vs 228 of 3506 [6.5%] in the control group; hazard ratio: 0.97; 95% CI: 0.81–1.17; p = 0.77). Despite inclusion of more than 7000 high-risk patients, HAT had insufficient people and so was statistically underpowered due to a markedly lower than anticipated mortality rate (1 vs 4% per annum). It was suggested that advances and high utilization of evidence-based secondary preventive therapies accounted for the low event rate.

Summary & conclusions

The theme of the 57th Annual Scientific Session of the American College of Cardiology was the demonstration that well accepted surrogate biomarkers of atherosclerosis and cardiovascular events are not always sufficient to predict atherosclerosis and cardiovascular events. Turning back recent efforts to ‘fast-track’ interventions based on an accepted change in a specific and presumably causal biomarker (LDL-cholesterol or blood pressure), it seems prudent to reverse course with reliance on evidence-based randomized clinical outcome trials. In the next few years, clinical outcomes data will be forthcoming with many of these agents investigated in atherosclerosis imaging trials in order to more accurately gauge whether imaging is a reliable tool for in the prediction of cardiovascular events

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.