Atherothrombosis is a generalized and progressive disease, involving endothelial dysfunction, leading to thrombosis, a manifestation of the disease, and resulting in cardiovascular events, stated Dr. L. Badimon Maestro of Barcelona, Spain. Systemic and local factors contribute to plaque rupture and about 35 of acute coronary events occur without disruption of the lipid-rich core.
Hypertension and hyperlipidemia are similar in regard to lesion development, with a linear relation between worsening of the condition and a higher grade of lesion type, according to unpublished data from a study by Badimon Maestro and colleagues of 125 patients undergoing heart transplantation. Family history, alcohol, and tobacco use did not show the same effect, in this study that sought to determine the relation between risk factors and development of atherothrombosis.
Other unpublished data from this group showed that hypertensive have a different cellular profile than normotensives, that is, much reduced volume of smooth muscle cells, increased number of monocytes, and lipids deposited either as general lipid content of LDL. Therefore, hypertension modifies vascular cell function in relation to lipids that lead to high-risk plaques.
New drugs, new targets being studied
New drugs are being sought that can stop growth of lipid-rich plaques and thrombus formation. Badimon Maestro reviewed several possible mechanisms and targets being studied.
Tissue factor is a main mechanism in platelet recruitment. Greatly elevated levels of tissue factor are found in the lipid-rich core of plaques, and it is expressed in the vascular wall and an isoform of tissue factor is involved in triggering of thrombosis. Fibrin, also involved in thrombosis, is dependent on the tissue factor pathway and contributes to destabilization of thrombus.
The thousands of receptors in the membrane of a platelet are candidates for interrupting activation. Possible types of drugs are receptor blockers, inhibitors of signaling, and ligand blockers.
Although aspirin has been the gold standard for antiplatelet therapy, many new molecules are in Phase I, II, and III research, including prasugrel, cangelor, and AZD6140, which can work through the ADP receptor, as does clopidogrel and ticlopidine. Clopidogrel is an oral AD receptor antagonist that is widely used clinically.
Badimon Maestro and colleagues are studying the use of a new family of nitric oxide (NO) donors for the inhibition of platelet deposition. They are using proteomic analysis to identify changes in the proteome associated with benefit or dysfunction seen in thrombosis. NO donors can modify filament and thereby affect platelet morphology and receptor function.
The protein gelsolin acts as an actin filament severing and capping protein, stated Badimon Maestro, and is required to modify the shape of the platelet a key step in the atherosclerotic process.
Despite the new drugs on the horizon and mechanisms and targets being studies, Badimon Maestro emphasized the need for global control of multiple risk factors that contribute to atherothrombotic risk, including hypertension.
Low-dose aspirin in well-treated hypertensives at different baseline cardiovascular risk
Although aspirin has been shown effective in secondary prevention to reduce myocardial infarction (MI) and stroke, its use for primary prevention remains controversial, stated Prof. Alberto Zanchetti of Milan, Italy. Of the six major studies of aspirin in primary prevention, published from 1988 to 2005, only the Hypertension Optimal Treatment (HOT) study was in patients with only hypertension. Zanchetti used data from the HOT study to answer open questions about the use of aspirin in hypertension.
In the HOT study, patients were randomized to one of three diastolic blood pressure (DBP) targets (≤90 mmHg, ≤85 mm Hg, ≤80 mm Hg), and patients were also randomized to aspirin or placebo. The HOT trial showed a 15% reduction in the primary endpoint of total cardiovascular events (CVE) and a 36% reduction in stroke in the patients taking aspirin and no effect on stroke.
Does aspirin interfere with the blood pressure lowering action of ACE inhibitors or other antihypertensive agents?
Zanchetti concluded there is no interference. In HOT, no effect was seen for systolic or diastolic blood pressures in relation to low-dose aspirin therapy, with the blood pressure reduction curves of the treatment and placebo arms super-imposable. Second step therapy in HOT was the addition of an ACE inhibitor and the reduction in total CVE and MI was similar in these patients.
Does aspirin worsen renal function?
Zanchetti concluded there was no concern regarding a worsening of renal function with low-dose aspirin in patients with hypertension. In HOT, the increase in serum creatinine was 1.06 mmol/l in the patients taking aspirin and 0.62 in placebo patients, and the estimated creatinine clearance -0.51 ml/min and 0.05 ml/min, respectively. Renal function worsened in 41 of the 7807 patients taking aspirin and in 51 of the 7789 patient taking placebo. In patients with serum creatinine greater than 115 micromolar, worsening of renal failure was similar (23 of 561 patients and 32 of 556 patients, respectively).
Does aspirin attenuate the CV benefit of ACE inhibitors, as suggested by a subanalysis of the SOLVD trial and CONSENSUS II trials in CHF?
Zanchetti stated that although the results from HOT show long-term (8 years) therapy with low-dose aspirin does not interfere with the blood pressure lowering effects of antihypertensive agents, including ACE inhibitors, these results cannot be extended to larger doses of aspirin or patients with congestive heart failure.
In whom is the benefit of aspirin greater than the harm?
Subgroup analyses from HOT, a single homogenous trial, suggest, Zanchetti stated, the greatest benefit is in patients with higher CV risk, in the range of 11-15 events/1000 patient years or greater, despite intensive treatment for hypertension. These analyses showed that in well-treated patients with hypertension, aspirin did not increase the risk of hemorrhagic stroke.
Recommendation for use of aspirin in patients with hypertension
Zanchetti recommended low-dose aspirin for patients with a moderate increase in serum creatinine, high global cardiovascular risk with high systolic or diastolic blood pressure at baseline. The ESH-ESC hypertension management guideline recommendations are:
- Antiplatelet therapy, in particular low-dose aspirin, for patients with prior CV disease events, if patients are not excessive risk of bleeding.
- In patients with hypertension, low-dose aspirin is beneficial in patients 50 years or older with a moderate increase in serum creatinine or a 10-year CV disease risk ≥20%.
- In patients with hypertension, low-dose aspirin therapy should be preceded by good blood pressure control.
The CHARISMA Study
Dr. A. Betriu Gibert of Barcelona, Spain presented the results of the CHARISMA study, which was first presented in March 2006 at the America College of Cardiology Annual Scientific Meeting.
CHARISMA assessed whether clopidogrel 75 mg daily is superior to placebo to prevent major ischemic events (stroke, MI, cardiovascular death) in high-risk patients 45 years and older who were receiving background standard therapy including low-dose aspirin. The evaluation of the safety of clopidogrel, measured by the incidence of fatal or severe bleeding, was a secondary objective.
Patients (n=15,603) were randomized to aspirin 75-182 mg/day ± clopidogrel (75 mg starting dose). Patients were followed every month for the first 3 months, and then every 6 months until the end of the study.
Inclusion criteria were patients 45 years or older with at least one documented vascular disease (coronary disease, cerebrovascular disease, symptomatic peripheral arterial disease), and/or multiple risk factors (two major or one major and two minor or three minor risk factors). Exclusion criteria were the requirement for clopidogrel, need for chronic therapy with a high-dose aspirin or non-steroidal anti-inflammatory drug (except COX-2 inhibitors), and current use of other oral anti-thrombotic medications.
The primary endpoints were the first occurrence of MI (fatal or nonfatal), stroke (fatal or nonfatal from any cause), CV death (including hemorrhagic death).
The principal secondary efficacy endpoint was the first occurrence of MI (fatal or nonfatal), stroke (fatal or nonfatal), CV death, or hospitalization for unstable angina, transischemic attack, or revascularization. Other efficacy endpoints were the components of the primary and secondary endpoints, and other safety endpoints were fatal bleeding, primary intracranial hemorrhage, and moderate bleeding (GUSTO definition).
Follow-up in the CHARISMA trial was about 94%.
CHARISMA was a negative study. The primary efficacy endpoint was 7.3% in the placebo plus aspirin arm and 6.8% in the clopidogrel plus aspirin arm (RRR 7.1%, p=0.22). A marginal benefit was seen for the principal secondary efficacy endpoint, 17.9% and 16.7% in the placebo plus aspirin arm and clopidogrel plus aspirin arm, respectively (RRR 7.7%, p=0.04).
There was a trend towards a higher rate of severe GUSTO bleeding in the clopidogrel plus aspirin group compared to the aspirin plus placebo group (130 vs 104 bleeds, RR 1.25, p=0.09). Significantly more moderate GUSTO bleeding was found in the clopidogrel plus aspirin patients compared to the placebo plus aspirin patients (164 vs 101 bleeds, RR 1.62, p<0.001).
The results for the primary efficacy endpoint were dependent on the category of inclusion. In the patients who qualified on the basis of CAD, CVD, or PAD (n=12, 153), there was a significant reduction in favor of clopidogrel plus aspirin (6.9% vs 7.9% for placebo plus aspirin, RR 12.5%, p=0.46). In the patients in CHARISMA on basis of multiple risk factors (n=3284), there was a trend against clopidogrel plus aspirin (6.6% vs 5.5% for placebo plus aspirin, RRR-20%, p=0.20).
In conclusion, overall, clopidogrel plus aspirin was not significantly more effect than aspirin alone in reducing the rate of CV death, MI, or stroke. There was a suggestion of benefit with clopidogrel plus aspirin in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors. These findings do not support the use of dual antiplatelet therapy across the broad population. Dual treatment should not be used in patients without a history of established vascular disease, but it could be beneficial in secondary prevention.