Two studies in the field of lipid therapy caused a stir at the ACC Congress in Chicago. HOPE-3 presented a pragmatic approach to primary prevention for discussion. The study showed that statins alone or in combination with antihypertensive therapy significantly reduced cardiovascular events in a group of intermediate-risk patients, without baseline or target LDL levels. GAUSS-3 substantiated the benefit of the PCSK9 inhibitor evolocumab in individuals with statin intolerance.
First, the much-discussed HOPE 3 study. The aim was to investigate the effects of primary prevention cholesterol and blood pressure lowering (alone or in combination) in a collective of patients without existing cardiovascular disease but with an intermediate risk of major cardiovascular events (approximately 1% annually). For this purpose, 12,705 patients were randomized into the following groups (median follow-up 5.6 years):
- Cholesterol lowering with rosuvastatin 10 mg/d (plus placebo) vs. double placebo
- Blood pressure lowering with candesartan 16 mg/d and hydrochlorothiazide 12.5 mg/d (plus placebo) vs. two-drug placebo
- Combination of above cholesterol and blood pressure lowering vs. dual placebo.
On average, the ethnically diverse participants, who came from 21 countries, were 65.8 years old, 46% female, and had baseline values of 138/82 mmHg (blood pressure), 128 mg/dl (LDL), and 45 mg/dl (HDL). No specific values were required as inclusion criteria; only risk determined inclusion in the study. Risk was defined as minimum age of 55 years in men and 65 years in women in combination with at least one CV risk factor such as abdominal obesity, smoking, or positive family history of CHD. Women aged 60 to 65 years were included if they had at least two risk factors.
Cholesterol reduction: LDL levels were on average 26.5% lower in the active treatment group than in the placebo group during the study. The first endpoint, consisting of cardiovascular death/myocardial infarction/stroke, yielded values of 3.7% (rosuvastatin) vs. 4.8% (placebo), corresponding to a significant risk reduction of 24% (NNT=91). The second endpoint, consisting of the above parameters plus resuscitation after cardiac arrest/cardiac failure/revascularization, showed the same trend (4.4% vs. 5.7%; HR 0.75; p<0.001). The effect was independent of baseline LDL values or blood pressure.
Blood pressure reduction: Blood pressure reduction was greater by an average of 6.0/3.0 mmHg in the active treatment group during the study. However, no significant differences were found for either the first or the second endpoint. Only patients with higher systolic blood pressure at baseline (>143.5 mmHg) showed significant benefits from antihypertensive therapy in both end points.
Combination: significant values were found for the combination of cholesterol and blood pressure lowering in each case, comparable to those with statin therapy alone (3.6% vs. 5.0; p=0.005 and 4.3% vs. 5.9%; p=0.003). The risk reduction was around 30% in each case. The authors noted that the combination was not worthwhile compared with statin therapy alone in patients with lower blood pressures (more symptomatic hypotension) but was in those with blood pressures in the upper third.
Confirmation of the new guidelines?
Individuals with intermediate CV risk benefit from statins in any case, but not from antihypertensives unless their blood pressure is relevantly elevated, HOPE-3 concluded. The study was criticized for having few mandatory physician visits and no dose titration. The reduction in cholesterol and blood pressure would probably have been greater if the response to the medication had been regularly monitored and the dose adjusted to the values. Overall, antihypertensive doses were low, which, according to the authors, was due to high-normal baseline values. It is possible that a higher dose would have shown a significant risk reduction. Furthermore, according to critics, it is unclear whether the use of other antihypertensives such as chlorthalidone or amlodipine would have led to opposite results.
At the same time, it was praised that the study was largely consistent with the recently modified lipid guidelines, as patients were not primarily selected and monitored according to lipid levels, but according to baseline risk for cardiovascular events. The results would support such a risk-based, simplified approach without target values in the area of statin therapy. The authors concluded that individuals with intermediate CV risk should receive statin therapy as primary prevention. In particular, because statin therapy was judged to be safe in the study.
In terms of blood pressure reduction, HOPE-3 tends to suggest that CV risk alone is not a determining factor. The actual level of blood pressure at onset has greater relevance. Or, to put it another way, all patients, regardless of baseline LDL or blood pressure levels, benefited from statin therapy, but only those participants who were actually hypertensive also benefited from the (additional) blood pressure reduction. Thus, individualization in primary prevention still seems to make sense here. The study was published in NEJM [1–3].
Statin intolerance – PCSK9 inhibitors as an alternative
In patients with muscle-related statin intolerance, the PCSK9 inhibitor evolocumab can be used safely and reliably: After 24 weeks, it significantly reduced LDL compared with ezetimibe, according to the main finding from GAUSS-3.
Statin intolerance due to muscle problems is relatively common in practice (up to 20%), but it is less common in studies, difficult to ascertain, and therefore controversial. To clarify ambiguities, statin tolerance was assessed separately in GAUSS-3 in a 10-week double-blind run-in phase in a cross-over design (phase A of the study). Intolerance, i.e., muscular side effects, was found in 209 of a total of 491 patients taking atorvastatin (20 mg) but not placebo. These 209 patients represented 42.6% of the total population. Muscle symptoms on statin were consequently common in the run-in phase.
However, such symptoms also occurred in 26.5% of patients who received placebo alone, indicating a considerable nocebo effect.
The authors emphasize that there is no clear diagnostic test for statin intolerance. Therefore, muscle symptoms can only be determined by the patient’s individual perception and the physician’s thorough history. Thus, separating physical intolerance from psychosomatic intolerance (under placebo) is difficult: Conversely, it may well be that more than 42.6% of patients experience muscle pain under statins but do not perceive it as relevant.
Since the total population of GAUSS-3 consisted exclusively of patients who had already been intolerant to two or more statins prior to the study, phase A brings another important finding: about half of the patients who were formerly intolerant were able to tolerate statins again in the study. Consequently, should statin therapy be tried repeatedly even in (formerly) statin intolerant patients? GAUSS-3 leaves the question open. However, there is plenty of room for discussion.
199 of the 209 intolerant patients and 19 subjects with significantly elevated creatine kinase levels who entered directly into the second phase received either evolocumab or ezetimibe (mean age 59 years, 49% female) in the second part of the study, which was also randomized. They administered either a subcutaneous monthly injection of 420 mg of evolocumab (plus placebo orally) or ezetimibe orally 10 mg/d (plus placebo as an injection) to the 218 patients in phase B in a double-blind fashion.
At the beginning of the second phase, LDL was 220 mg/dl. 32% of patients had CHD. Evolocumab was significantly superior to ezetimibe in both the first and second co-primary endpoints: At week 24, the mean reduction in LDL was -52.8% vs. -16.7% (p<0.001). When week 22 and 24 were taken together, values of -54.5% vs. -16.7% were obtained (p<0.001). The targeted LDL level of <70 mg/dl was achieved by almost 30% of patients on evolocumab vs. 1.4% on ezetimibe (p<0.001). Thus, it is noteworthy that a majority of patients did not reach the target value even under evolocumab. Lipoprotein(a) was significantly more reduced and HDL significantly more increased under the PCSK9 inhibitor. Muscular side effects occurred in 20.7% vs. 28.8% (p>0.05), but the discontinuation rate due to these problems was very low with evolocumab (0.7% vs. 6.8%), suggesting PCSK9 inhibitors as a valid alternative in documented muscular statin intolerance. Admittedly, they are not approved for this indication. The cost-benefit balance and long-term effects in the prevention of CV events are also not yet clear. Many experts at the congress warned that statins should not be abandoned prematurely. The study was published in JAMA [4].
Source: American College of Cardiology (ACC) 2016 Scientific Sessions, April 2-4, 2016, Chicago.
Literature:
- Yusuf S, et al: Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease. NEJM 2016 April 2. DOI: 10.1056/NEJMoa160017 [Epub ahead of Print].
- Lonn EM, et al: Blood-Pressure Lowering in Intermediate-Risk Persons without Cardiovascular Disease. NEJM 2016 April 2. DOI: 10.1056/NEJMoa1600175 [Epub ahead of Print].
- Yusuf S, et al: Blood-Pressure and Cholesterol Lowering in Persons without Cardiovascular Disease. NEJM 2016 April 2. DOI: 10.1056/NEJMoa1600177 [Epub ahead of Print].
- Nissen SE, et al: Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance. JAMA 2016 April 3. DOI: 10.1001/jama.2016.3608 [Epub ahead of Print].
CARDIOVASC 2016; 15(3): 36-38
