Patient at intermediate cardiovascular risk: statins, yes! - antihypertensive therapy, maybe.

Abstract

Uncontrolled arterial hypertension and high levels of low density lipoprotein (LDL) cholesterol are undoubtedly the most common and important modifiable cardiovascular risk factors. Many prospective trial demonstrated definitely that the treatment of these two conditions significantly reduced the occurrence of adverse cardiovascular events in high-risk patients, such that their treatment has become the cornerstone of modern cardiovascular prevention. Nonetheless, because the population most often affected with adverse cardiovascular events has an intermediate risk, that is without a previous history of cardiovascular disease (predicted cardiovascular risk of 1–5% according to the SCORE model),1 one of the most pressing and debated issues is to establish, with scientific rigor, the appropriate threshold for antihypertensive and cholesterol-lowering treatment in primary prevention settings, as well as the therapeutic targets to be aimed at in this large population of patients. Life-style modification represents the ideal first step in primary prevention settings, because of its low cost, and the ease and safety of its implementation. Nonetheless, a number of studies failed to demonstrate a significant reduction of major cardiovascular events, mainly because significant life-style changes are difficult to implement and sustain in the long term.2 An important alternative would be the use of safe and effective drug therapy, presently available at very low cost, proven to reduce adverse cardiovascular events for intermediate risk patients. The HOPE 3 study (Heart Outcomes Prevention Evaluation), published in 2016 and presented at the American College of Cardiology annual meeting, was conceived with these premises. The trial started in 2007 and was aimed at the evaluation of the efficacy and safety of a moderate dose of a powerful statin versus placebo, a fixed combination of moderate dose of angiotensin II receptor antagonist and diuretic versus placebo, and a combination of both treatments versus double placebo in prevention of major cardiovascular events (without predetermined therapeutic targets). This was an international, prospective, randomized controlled trial, which enrolled 12 705 patients with at least one cardiovascular risk factor but without a positive clinical history for cardiovascular disease. After a 4-week run-in phase during which patients received both antihypertensive (candesartan 16 mg/hydrochlorothiazide 12.5 mg/od) and lipid-lowering (rosuvastatin 10 mg/od) treatment, all patients were randomized according to 2 × 2 factorial study design. Follow-up visits occurred every 6 months for 5–6 years (mean duration of the follow-up). The co-primary end-point included cardiovascular deaths, and nonfatal myocardial infarction (MI) and/or stroke; the second co-primary end-point was the combination of cardiac arrest with successful resuscitation, heart failure, and coronary revascularization. The mean basal LDL cholesterol values were 128 mg/dl and 138/82 mmHg for arterial blood pressure. The LDL cholesterol reduction during the trial was of 33.7 mg/dl and 6.2/3 mmHg for blood pressure. In the study arm evaluating rosuvastatin 10 mg od both primary end-points were significantly lower in the treatment group (P = 0.002 and P < 0.001, respectively). A significant reduction of the risk of cardiovascular events (24%) was also demonstrated, confirming, in a later subanalysis, the benefit and safety of statin treatment in all subgroups of hypertensive patients and value of basal c-LDL.3 These results support the recommendation of the recent European Guidelines for prevention of cardiovascular disease, which encourages pharmacological treatment for patients at intermediate risk, with c-LDL value higher than 100 mg/dl, which is also considered the therapeutic target.4 The American College of Cardiology/American Heart Association 2013 Guidelines already suggested a similar approach: statin treatment was recommended in primary prevention regardless of the c-LDL level in patients with a risk of adverse cardiovascular events higher than 7.5%, according to the Framingham-based algorithm, which corresponds to a 2.5% risk of cardiovascular death at 10 years according to the SCORE model.5 A correct evaluation of the total cardiovascular risk is then paramount in the selection of patients potentially benefiting from treatment with statins and should be part of the routine assessment by every physician. In the hypertensive arm of the HOPE 3 study the candersartan/hydrochlorothiazide treatment did not result in reduction of primary end-points (4.1 versus 4.4%). In a subsequent analysis of three subgroups, according to the baseline SBP values, a statistically significant benefit (occurrence of cardiovascular events 4.8 versus 6.5%) was recorded for the third group, that is for patients with baseline systolic pressure higher than 143.5 mmHg.6 These results could help define the threshold for SBP (<140 mmHg) vis-à-vis cardiovascular risk (<5%) under which pharmacological treatments aimed at blood pressure lowering are not useful at least in the short mid-term. Furthermore, none of the antihypertensive drugs used in this trial has been shown in previous studies to reduce the risk of cardiovascular events at the dosage used in this study, and during the time span of follow-up. Accordingly, a benefit of this treatment could not be ruled out in the other subgroups with higher drug dosage used for longer periods of time. At variance with the HOPE 3, the 2015 SPRINT study (Systolic Blood Pressure Intervention Trial),7 examined the effect of a more rigorous antihypertensive treatment (as compared with present recommendations), aiming at a target SBP lower than 120 mmHg. The trial enrolled patients with SBP higher than 130 mmHg, at intermediate/high cardiovascular risk, no diabetes mellitus, and no previous stroke or polycystic renal disease. The study patients were randomized into two groups according to treatment strategy, standard or intensive, with SBP target lower than 140 mmHg and lower than 120 mmHg respectively. The study revealed a significant 25% reduction in the occurrence of the composite primary outcome (acute MI, acute coronary syndrome, stroke, heart failure, and cardiovascular mortality), 43% reduction for cardiovascular mortality, 27% for all-cause mortality, and 38% decrease in hospital admission for heart failure in the group receiving intensive treatment (mean number of drugs needed 2.7) as compared with the standard treatment group (mean number of drugs needed 1.8), with an achieved target blood pressure at 1 year of 121.4 and 136.2 mmHg, respectively. These results overpowered the potential adverse effect (decreased renal function, electrolytes unbalance, and hypotension) of such intensive treatment. It must be stated that some experts criticized the clinical impact of the SPRINT study, namely the extensive use of high doses diuretics, chlortalidone and loop diuretics, as being the main driver for the beneficial effects experienced by the intensive treatment group, particularly as it pertains to the decrease in the incidence of heart failure. In fact, the group treated with a standard antihypertensive regimen received a limited amount of diuretics to prevent the lowering of SBP below 130 mmHg. The two trials present important differences, mainly regarding the baseline characteristics of the population enrolled and the context in which the blood pressure was measured during the follow-up. About 20% of the participants in the SPRING trial had a history of cardiovascular disease, whether those patients were excluded from the HOPE 3 study. The HOPE 3 and the SPRING population differed as far as ethnicity (African American <2 versus 31%, respectively) and baseline use of antihypertensive drugs (22 versus 90%, respectively). Furthermore, the elderly (>75 years) derived the most benefits from the intensive antihypertensive regimen, making the SPRINT trial more representative, demographically, of the general population. Another remarkable difference between the two trials is the not well justified exclusion from the SPRING study of patients with diabetes mellitus. The intensity of the pharmacological treatment was also different: at variance from the SPRING the HOPE 3 protocol did not require the titration of the drug toward a specific blood pressure target.8 Patients at intermediate-high risk, similar to the SPRING patients, could be eligible for a more intensive treatment. The patients enrolled in the SPRING trial were a very selected group, such that it is difficult to extrapolate the results to the general population of hypertensive patients, considering also that diabetic and patients with previous stroke were excluded. To overcame these drawbacks another study should be considered, still with the same objective (comparing the standard and intensive blood pressure treatment regimen), but also including intensive glucose and cholesterol-lowering treatment: the ACCORD study (Action to Control Cardiovascular Risk in Diabetes) was designed with these premises, but its results were not statistically significant, and did not support lower blood pressure targets to achieve higher therapeutic benefits. In the intensive treatment group, the occurrence of nonfatal MI was lower, but overall cardiovascular mortality was higher (P = 0.02). The-all cause mortality rate was also higher for the intensive treatment group. The reverse trend was found concerning the occurrence of stroke, 41% lower in the intensive treatment compared with the standard group.9 It is clear that the results of the SPRING trial raised significant interest, but also some concerns. Among specific cardiovascular outcomes, stroke and MI were not significantly lower in the group treated with an intensive blood pressure-lowering regimen (in the vast majority of study stroke is the specific outcome more favorably affected by blood pressure lowering). Furthermore, the blood pressure measuring technique adopted in the SPRING trial was at variance from what is commonly used in clinical practice, recommended by guidelines, and used in all other trials: blood pressure was recorded with automated recording devices, without nursing/medical supervision (to prevent the ‘white coat’ effect). As a consequence, it could be inferred that should the blood pressure had been measured with the standard technique, the blood pressure values of the SPRING trial would have been closer to the 130 mmHg, consistent with the results of recent large meta-analysis, supporting a target SBP lower than 130 mmHg.10 International guidelines for the treatment of hypertension recommend a blood pressure target lower than 140/90 mmHg. Considering the general population, along with the evidence derived from the HOPE 3 and SPRINT trials, and the recent meta-analysis and clinical studies, the International Society of Hypertension recommends to aim for a target SBP of lower than 130 mmHg, whenever this is possible without incurring in treatment adverse effects, for the majority of patients affected with hypertension. There are no data definitely supporting a blood pressure target lower than 120 mmHg in clinical practice, also for patients at an intermediate–high cardiovascular risk.11 Acknowledgements Conflicts of interest There are no conflicts of interest.