A lecture on the mechanisms of interaction between antihypertensive agents and statins by Dr. J. Egido from Madrid, Spain, provided the foundation for a presentation of results from an extended analysis of the ASCOT-LLA study.
Egido reminded the audience that more than 50% of patients with hypertension have dyslipidemia, yet a low number are being treated for both, as shown by at least three population surveys. The MRFIT study showed a linear relation between coronary heart disease (CHD) mortality and achieved levels of systolic blood pressure (SBP) and total cholesterol. At least one population survey has shown that only about 40% of patients achieve the recommended goals for both blood pressure and total cholesterol.
He suggested that a single pill with both a blood pressure and lipid lowering agent would increase the number of patients being treated for both conditions and thereby reduce the risk of cardiovascular events in these patients. The 14-week GEMINI study in a primary care setting showed that with treatment with a single combination tablet 58% of patients had achieved the goals for blood pressure and LDL cholesterol and that 76% of patients with coronary heart disease or its equivalent achieved both goals.
Synergistic effects between blood pressure lowering drugs and statins
Antihypertensive drugs and statins have synergistic effects modulating some mechanisms involved in vascular injury, and these were reviewed by Egido.
Endothelial function is disturbed by both hypertension and dyslipidemia. Specifically, these conditions cause a decrease in nitric oxide synthesis and increases in endothelin, radical oxygen species, COX activity and leukocyte adhesion, which lead to vasoconstriction, cell proliferation, inflammation, and thrombosis, and ultimately lead to atherosclerosis.
Statins have vascular protective effects, with major trials showing about a 30% reduction in major coronary events, coronary mortality, and total mortality, and have been shown effective for secondary protection in patients with normal cholesterol levels. The vascular protective effects of statins include positive effects on endothelial dysfunction, inflammation, cell proliferation and migration, immunomodulation, thrombosis, and angiogenesis, and statins contribute to plaque stabilization and possibly to plaque regression. In regard to inflammation, statins have been shown to decrease C-reactive protein and cytokines.
Effective treatment combinations for reducing CV events
Egido suggested that the early (6 months) reduction in events in the ASCOT-LLA study was due to the positive effects of atorvastatin on endothelial dysfunction and inflammation, effects that have been shown in basis science studies such as the AITOR study.
The combination of an ACE inhibitor or angiotensin receptor blocker (ARBs) plus a statin or a calcium channel blocker (CCB) plus a statin are effective combinations based on study data, some of which was reviewed by Egido.
Hypercholesterolemia induces overexpession of AT1 receptors and enhances the biological effects of Angiotesin II. A review of basic science studies by Egido showed that statins interrupt many different pathways in the “hypertension-lipid network.” ARBs have been shown to reduce neointimal formation in mice and atherosclerotic lesions, among other positive effects.
CCBs have several known anti-atherosclerotic effects, including inhibition of smooth muscle cells, migration and proliferation; enhancement of endothelial nitric oxide production, lipid antioxidant activity, improved endothelial cell cytoprotection, and remodeling of atherosclerotic membrane structure. Most of the data has been demonstrated with amlodipine. CCBs have also been shown to have anti-inflammatory effects.
Small artery compliance and systemic vascular resistance were improved in patients with hypertension and hyperlipidemia with the combination of amlodipine and atorvastatin, demonstrating its additive effects. Further, this combination was also shown to improve fibrinolysis in patients with hypertension, hyperlipidemia, and insulin resistance. A study in mine has shown plaque regression of 43% with amlodipine, 80% with atorvastatin, and 93% with amlodipine plus atorvasatin. This combination has also been shown in new data to modulate the profile of proteins released by human atherosclerotic plaques.
Hence, Egido concluded that treatment of both hypertension and hyperlipidemia with newer antihypertensive agents plus a statin, particularly, in one tablet, are effective treatment recommendations and are most cardioprotective.
Interaction between antihypertensive and statin therapy in the ASCOT study
Dr. Bjorn Dahlof from Goteborg, Sweden, reviewed the main results of the ASCOT blood pressure and lipid lowering arms, which have been previously reported.
The ASCOT trial compared the effect of a standard antihypertensive regimen (the beta blocker atenolol and/or a thiazide diuretic) and a contemporary regimen (the calcium channel blocker amlodipine and/or ACE inhibitor perindopril) and the effect of the lipid lowering agent atorvastation versus placebo in patients with a total cholesterol > 250 mg/dL on the primary endpoint of non-fatal myocardial infarction (MI) and fatal CHD. In this PROBE design study, 19,257 patients were randomized in the blood pressure lowering arm (BPLA) and 10,305 in the lipid lowering arm (LLA) in a 2×2 factorial design.
In LLA, at the end of the study, there was a difference of about 12 mmol between the two arms for total and LDL cholesterol.
The main results were a reduction in the primary endpoint of 36%, stroke (fatal and nonfatal) by 27%, and all cardiovascular events and procedures by 21% with the amlodipine-based regimen compared to the atenolol-based regimen.
Dahlof noted that these reductions were achieved in patients with a level of risk less than in the LIFE, HOPE, VALUE and ALLHAT trials.
The relative risk reductions were greater in the combined BPLA and LLA arms:
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A greater reduction with atorvastatin was seen with the amlodipine-based treatment (53% versus placebo) compared to atenolol-based treatment (16% versus placebo) for the primary endpoint. A similar trend was seen for stroke (fatal and nonfatal) and for total CV events and procedures.
A formal test for interaction between lipid-lowering and blood pressure lowering was of borderline statistical significance for fatal MI and nonfatal CHD. There was no significant interaction for total CV events and procedures and fatal and nonfatal stroke.
This could be a chance finding, but there is plausible biological explanation for a synergistic effect between atorvastatin and amlodipine-based treatment on acute coronary events, stated Dahlof.
New aspects of the ASCOT study
Dr. Peter Sever from London, England, stated there were three key messages from the ASCOT study:
- Early and effective BP lowering rapidly reduces CV event rate, stroke by 35% and CHD events by 35%.
- Atorvastatin confers substantial additional benefits on CHD and stroke reduction.
- Newer amlodipine-based regimen confers additional advantages over older atenolol-based regimen on CHD and stroke.
- The “global” benefit is estimated to be a reduction in both CHD and stroke of about 65% or more with both lipid and blood pressure reduction.
Sever reviews results from an extended follow-up of the ASCOT-LLA patients after LLA was closed prematurely at 3.3 years. The patients who had been in the placebo arm were offered atorvastatin and the patients on atorvastatin were followed until the end of ASCOT-BPLA, a median of 5.5 years.
A 50% drop-in rate and a 50% drop-out rate to atorvastatin were found in the LLA-extended data:
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At 5.5 years, an identical reduction on total and LDL cholesterol was found in both arms, with a reduction in patients assigned to the stating and an increase in the patients who discontinued the stating.
This extended analysis also revealed that despite the “enormous cross over” between atorvastatin treatment and placebo, the relative risk reductions remained the same for the primary endpoint and a “risk reduction virtually identical” for the secondary and tertiary outcomes. A doubling of events was seen between the two time points examined. Specific results are shown in Table 1.
Table 1. Risk reductions and number of events at 3.3 and 5.5 years
in the extended analysis of ASCOT-LLA
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Sever stated that the predicted number of events if LLA had continued were those found in this analysis of events at 3.3 and 5.5 years. For statin-treated patients, 165 events were predicted and 163 occurred, and for placebo-treated patients, 258 events were predicted and 249 occurred.
Sever suggested there must a “carry over” effect of atorvastatin even after it is discontinued, because a greater risk reduction in outcomes was found than would be predicted considering the 50% drop in and drop out rate and the expected 30% relative risk reduction for patients new to atorvastatin. They found that in patients originally assigned to atorvastatin but who discontinued it, the event rate continued to fall over the 5.5 years, suggesting a carry over effect from the drug. There was some reduction in the placebo patients over this time, but not as much as expected.
Thus, Sever concluded:
- The benefit of atorvastatin continued over the additional 2.2 years, despite the 50% crossover in each arm.
- Even assuming early benefits for patients crossing over to active treatment and lipid profiles equalizing, the continuing benefit of atorvastatin in patients no longer taking it probably accounts for maintenance and continuing substantial benefits in patients originally assigned to a statin.
Statin treatment in most patients with hypertension will confer substantial and cost effect benefits on cardiovascular outcomes.