Cardiovascular diseases (CVD) are the leading cause of mortality, premature deaths, and morbidity in Europe and worldwide, with a substantial contribution to economic and human costs of health care . The major medical risk factors associated with CVD are high blood pressure (BP), high total cholesterol levels, high BMI, and high fasting plasma glucose. Among them, high BP and high total cholesterol levels make the greatest average contribution to the CVD burden (56 and 30% of attributable deaths), while the contribution of high BMI and hyperglycemia is more modest (less than 20%) . These uphold the priorital need to effectively control the risk factor profile at the level of the general population. This control must be extremely tight in individuals with an established CVD to minimize as much as possible their greater risk of recurrent cardiovascular events (secondary prevention). There is also, however, the need to reduce the risk of the first event among individuals without a previous CVD, particularly if the risk of developing an event is high (primary prevention) .
Epidemiological studies show that risk factors frequently cluster in individuals, with, for instance, only 10–20% of cases of hypertension occurring in the absence of other CVD risk factors. This has implications for disease management, in particular in secondary prevention, as when several risk factors need to be addressed from a multifactorial approach, complex medication regimens and a high number of different drug classes need to be prescribed .
As recommended by current guidelines [3–7] in addition to lifestyle changes, the gold standard pharmacological treatment for high-risk patients with established CVD is the administration of: statins, alone or combined with ezetimibe or proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i) to achieve target lipid levels, that is, those that effectively counteract atherogenic dyslipidemia; antihypertensive agents (usually two or more) to be chosen among five major drug classes [i.e. angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers, calcium channel blockers (CCBs) and diuretics (thiazides and thiazide-like)]; antiplatelet therapy to prevent thrombosis, in particular low-dose aspirin (75–100 mg); and glucose-lowering drugs (usually more than one).
CARDIOVASCULAR RISK FACTORS CONTROL IN CLINICAL TRIALS AND THE REAL LIFE
Randomized controlled trials (RCTs) have shown that current treatments can effectively control the most important risk factors in the majority of the recruited participants. This is favoured, however, by the fact that trials are conducted in a highly controlled environment in which adherence to the prescribed treatment regimen is maximized and therapeutic inertia (failure to adequate the dose or change treatment in case of ineffectiveness) is reduced at a minimum. In addition, vulnerable patients and those with comorbidities are often excluded in trials to avoid making the treatment strategies too complex and loosing patients for reasons that are outside the main study endpoints . Conversely, in the context of real-world clinical practice, adherence is usually low, therapeutic inertia is high and patients are highly diversified for their clinical patterns, which makes optimal disease control elusive for a significant proportion of patients. Indeed, several surveys conducted worldwide have shown that a substantial proportion of patients in both primary and secondary CVD prevention fail to achieve control of their blood pressure (BP), lipid and glucose levels as recommended by current guidelines [9–13]. For instance, the PURE (Prospective Urban Rural Epidemiology) study, a survey that included a variety of countries, BP control was seen in only 13% of hypertensive patients, only 25% of patients on secondary CVD prevention were taking antiplatelet drugs, 17% beta-blockers, 20% ACEIs or ARBs and 15% statins .
Moreover, although cardiovascular risk factor control is particularly low in primary prevention, secondary prevention is by no means immune by the problem. The EUROASPIRE (European Action on Secondary and Primary Prevention through Intervention to Reduce Events) surveys have consistently reported that most hospitalized coronary patients do not achieve the target values recommended by guidelines for the different risk factors in spite of the treatment prescription in a more controlled setting than that used for individuals on primary prevention. In the latest survey performed only a few years ago, 42% of patients still had high BP, 71% had high LDL-cholesterol and 29% were reported having uncontrolled diabetes . Moreover, a study conducted in Australian primary care showed that only 50% of patients with an established CVD were prescribed a combination of BP-lowering medication, a statin and an antiplatelet agent, whereas 9% were prescribed a BP-lowering agent and a statin, but not an antiplatelet agent . Similarly, the PURE study found that less than 50% of patients with CVD worldwide (and less than 10% of patients in low-income countries) received the three or more proven effective drugs for secondary prevention [10,15].
LOW ADHERENCE TO TREATMENT AS A MAIN FACTOR FOR INSUFFICIENT CONTROL OF CARDIOVASCULAR RISK FACTORS
The above studies highlight that in individuals with a multifactorial risk profile achieving simultaneous control of all risk factors is neither easy nor always feasible. Indeed, evidence is available that in a multiple risk factor setting, control of single risk factors is rarer than that seen in individuals who present with one risk factor only. In this context, there is a general agreement that this is due not so much to poor clinical effectiveness but rather to poor adherence to prescribed treatment regimens and to physicians’ therapeutic inertia. Indeed, studies that have used different methods to measure adherence to treatment have invariably concluded that optimal adherence is exceptionally rare and that in a large number of patients drugs are not assumed for many shorter or longer periods, with an average time covered by the prescribed drugs not greater than 50% of the overall treatment duration. This is true for BP-lowering agents, for statins and also for antiplatelet agents .
A well-known consequence of poor adherence to treatment is that uncontrolled risk factors lead to an increased risk of recurrent or new cardiovascular events, with an increase of all-cause mortality as well [17–19]. Adherence depends on several demographic, personality and clinical factors, the therapy-related ones being among the most important. The aim of the article was not to perform a systematic review on all causes of poor adherence but to focus only in one of the well known and accepted causes that may be managed by doctors in the clinical setting, that is the positive relationship between the number of pills and poor adherence. These constitute not only side effects, duration of therapy, and frequent changes in medication regimen but also the complexity of the medication regimen, that is, the doses the timing and the number of the concurrent medications to be taken daily . Systematic reviews and meta-analyses have consistently shown that the adherence of patients on chronic CVD medications decline with polypharmacy and increased dosing frequency, such as for example once versus twice or more daily [18,20–22]. Therapeutic inertia is another barrier to the use of cardiovascular medications, almost certainly contributing to a relevant degree to the low clinical effectiveness of pharmacological treatment. Up to 85% of primary care visits for hypertension control and 80% for dyslipidemia control face the problem of therapeutic inertia [23,24]. Of note, therapeutic inertia has recently been shown to also have a relationship with cardiovascular outcomes and its adverse consequence for the management of diabetes, hypertension, and lipid disorders has been estimated to contribute to up to 80% of heart attacks and strokes .
THE ROLE OF THE ‘POLYPILLS’ IN IMPROVING ADHERENCE TO TREATMENT
The above drawbacks, low adherence to treatment in particular, lead to the development of ‘polypills’, that is, tablets incorporating drugs active in different cardiovascular risk factors, that could both increase the efficiency of the pharmacological treatment and decrease cardiovascular morbidity and mortality via the increase of treatment adherence brought about by treatment simplification [26,27]. This approach is nowadays endorsed by some clinical guidelines, such as the current European and US hypertension guidelines [28,29], the European guidelines for the management of myocardial infarction , or the European Society of Cardiology (ESC) guidelines for the prevention of CVD . There are currently different marketed versions of the cardiovascular polypill, in its more common of a minimal composition of a statin, an antiplatelet drug (commonly aspirin) and an antihypertensive agent (ACEI/ARB/thiazide/β-blocker/CCB) .
In the scenario of CVD secondary prevention, the polypill strategy has been shown to reduce SBP and low-density lipoprotein (LDL) cholesterol compared with usual care or with medications administered separately. It has also been shown to be well tolerated and cost-effective [30–34]. Moreover, a recent meta-analysis of observational studies in patients with CVD has shown that evidence-based combination pharmacotherapy might reduce the risk of all-cause mortality by approximately 40% and major cardiovascular events by 25–30% compared with no therapy or monotherapy . In addition, a meta-analysis of RCTs has reported that, in patients with established CVD, the likelihood to achieve of all three recommended ESC guideline targets (BP, LDL-cholesterol and in absence of markers of antiplatelet drug efficacy, increased adherence to antiplatelet therapy) was higher among patients on polypill therapy than among those on usual care (24 versus 19%), this being particularly true for those undertreated at baseline . In addition, partial nonadherence is much more common than full nonadherence and patients are used to show a selective attitude based on their own feelings. If a nonadherent patient decides to stop the intake of the polypill this will in fact result in simultaneous discontinuation of all three drugs. Although this indeed appears as a real risk, all studies comparing multiple pill treatments versus a polypill-based treatment showed a significant improvement in adherence and in BP control. Therefore, even considering that the individual risk exists for a given patient of being nonadherent to the polypill, the overall improvement in adherence and BP control is expected in the vast majority of patients. It is also conceivable that the use of the polypill help to overcome therapeutic inertia, as the fixed-dose components of the polypill circumvent the problem of separately titrating each of them, with an undue prolongation of the titration phase and a negative reflection on patient's psychology and confidence in the doctor.
As far as hypertension is concerned, the level at which the on-treatment BP is regarded as optimal varies with age (lower in younger than in older patients), the patient's clinical condition (higher in chronic kidney disease and possibly in coronary disease) and the cardiovascular risk score, which is heavily influenced by history of cardiovascular events, asymptomatic organ damage and clustering of high BP with other risk factors (e.g. dyslipidemia and metabolic syndrome), a condition that may increase overall cardiovascular risk up to three-fold to four-fold the risk of a cardiovascular event compared with hypertension alone . The recommendation of the recent ESC/ESH hypertension guidelines is to initiate treatment with a combination of two BP-lowering drugs in a single pill regardless of the cardiovascular risk, to uptitrate treatment to three drugs if needed, also in a single pill, to prescribe a statin in patients with established CVD or at moderate or high cardiovascular risk, and to add an antiplatelet agent only among those with established CVD . This appears to be in line with the polypill developed by the Centro Nacional de Investigaciones Cardiovasculares (CNIC) of the Ministerio de Ciencia e Innovación de España containing aspirin, ramipril (ACEI) and atorvastatin (statin). The CNIC polypill is the only cardiovascular polypill containing aspirin approved by the European Medicines Agency (EMA) and marketed in Europe for the secondary prevention of CVD [27,38].
SECONDARY VERSUS PRIMARY PREVENTION OF CARDIOVASCULAR DISEASE
Antiplatelet drugs, such as aspirin at low doses indisputably represent a cornerstone of the treatment of individuals at very high cardiovascular risk, such as those with a previous cardiovascular event. In contrast, use of low-dose aspirin in primary CVD prevention has been and still is a matter of debate as several meta-analyses fail to show that the aspirin-related reduction of thrombotic outcomes is clearly greater than the aspirin-dependent inconveniences, such as minor or major bleedings . A recent systematic review and meta-analysis of RCTs found that the use of aspirin in patients without established CVD was associated with a lower risk of cardiovascular events (absolute risk reduction 0.38%) and a slightly greater increase risk of major bleedings (absolute risk increase 0.47%) . This has led the 2018 ESC/ESH guidelines for the management of arterial hypertension, and also the 2016 European guidelines on CVD prevention to recommend low-dose aspirin only for secondary and not for primary prevention [3,28]. However, the ESC guidelines on diabetes, prediabetes, and CVD developed in collaboration with the European Association for the Study of Diabetes (EASD) have recently recommended the use of low-dose aspirin in patients with diabetes mellitus even in absence of a history of CVD, thereby extending antiplatelet treatment to patients with a high risk in the absence of clear contraindications still in the area of primary prevention of CVD . Similarly, the 2019 guidelines of the American College of Cardiology/American Heart Association (ACC/AHA) on the primary prevention of CVD recommend routine use of low-dose aspirin also for primary prevention of atherosclerotic CVD in adults aged 40–70 years in whom cardiovascular risk is high and no increased risk of bleeding is detected, the decision being reached on an individual basis in those older than 70 years at no increased risk of bleeding . Thus, based on these recommendations, in patients at high CVD risk with no clinical evidence of a previous cardiovascular event and no significant risk of major bleeding, the use of the polypill that includes a low dose of aspirin can be considered. Along this line, a recent study conducted in Iran has assessed the effectiveness of a four-component polypill (aspirin, atorvastatin, hydrochlorothiazide, and either enalapril or valsartan) compared with minimal care (nonpharmacological preventive intervention) in patients treated for secondary or primary prevention. The results showed that, after 5 years of follow-up, patients treated with the polypill had less risk of cardiovascular events than patients on minimal care regardless of the absence or presence of pre-existing CVD. The rate of bleeding was similar between the two groups .
THE PROBLEMS OF THE ‘POLYPILLS’ USE IN CLINICAL PRACTICE
When starting a cardiovascular polypill to facilitate treatment of patients with hypertension, dyslipidemia and prior CVD, a practical problem may be that the doses of the antihypertensive drug and the statin must be adapted to the hypertension grade and the LDL-cholesterol level of the patient, which may vary widely between patients even showing a similar cardiovascular global risk. However, this is nowadays no more a major problem as multiple versions of the cardiovascular polypill with different doses of the BP-lowering and statin components are currently available, thus allowing for a greater flexibility of its prescription and use.
On the basis of extensive data on the therapeutic interchangeability between statins as well as between renin–angiotensin system (RAS) blockers, either ACEIs or ARBs, switching between different versions of the cardiovascular polypill does not represent a major problem. Nevertheless, on the following part of this review, we provide tables that may help physicians to correctly do so, based on information on equivalent effective doses. Moreover, we provide treatment algorithms and details on the available cardiovascular polypill, on their indications in patients with high BP and prior CVD and on how to associate to a polypill other BP-lowering or lipid-lowering drugs if needed. Finally, we give advice on how to switch and adapt the treatment with fixed-dose combinations of antihypertensive medications when use of the cardiovascular polypill regimen may seem preferable. As in European countries, the only currently marketed cardiovascular polypill is the CNIC polypill containing ramipril and atorvastatin, a specific reference is made in order to initiate the cardiovascular polypill regimen.
HOW TO SWITCH FROM OTHER RENIN–ANGIOTENSIN BLOCKERS OR STATINS TO THE INDIVIDUAL COMPONENTS OF THE CNIC POLYPILL (RAMIPRIL AND ATORVASTATIN)
There are currently six different versions of the CNIC polypill, all of them with the same components, namely 100 mg of acetylsalicylic acid, two possible doses of atorvastatin (20 or 40 mg) and three possible doses of ramipril (2.5, 5 or 10 mg).
Switching from other angiotensin-converting enzyme inhibitors or angiotensin receptor blockers to ramipril
In general, clinical guidelines on hypertension recommend prescribing: ACEIs or ARBs as drug classes to lower BP without specifying a particular drug; and ARBs in case of intolerance to ACEIs; and no ACEIs and ARBs together in combination treatments . All ACEIs have a similar BP-lowering efficacy, safety and degree of cardiovascular protection. In patients taking an ACEi without side effects, it may be discontinued and initiate a different ACEI at a comparable dose the following day. The approximate equivalent effective daily doses of the various ACEIs with respect to ramipril are shown in Table 1, based on the data of the Federal Union of German Associations of Pharmacists (ABDA) .
Concerning ARBs, in general there is no problem in substituting one ARB with one ACEI (of course in absence of ACEI intolerance), but available dose equivalent data must also be considered. The approximate equivalent effective daily doses of ARBs with respect to ramipril are shown in Table 2 based on published data .
Switching from other statins to atorvastatin
Clinical guidelines emphasize that cardiovascular protection has been documented for several statins in both secondary and primary prevention scenarios [45,46] with positive data in hypertensive patients as well . They also emphasize, however, that cardiovascular outcomes and mortality continue to decrease down to low achieved blood cholesterol levels, which gives the relationship between on-treatment cholesterol and cardiovascular protection ‘the lower the better’, appearance different from what is the case for the relationship between BP and cardiovascular protection; based on available evidence, the LDL-cholesterol goal to achieve with treatment are higher in primary (<115 mg/dl in low risk patients and <100 mg/dl in moderate-risk patients) compared with secondary prevention, in which the recommended target value is 70 mg/dl for high-risk patients and <55 mg/dl for very high-risk patients ; and at variance from antihypertensive drugs, statins show considerable differences in their ability to reduce LDL-cholesterol [48–51].
Several studies have addressed the question of how to select the optimal lipid-lowering treatment to achieve the optimal lipid target based on the basal level of LDL-cholesterol, the overall cardiovascular risk and the primary or secondary prevention setting, with a detailed reference to different statins and their posology [50,51]. On the basis of their lipid-lowering power, statins are divided in high-intensity (LDL-cholesterol reduction >40%); moderate intensity (31–40% reduction); and low-intensity lowers (<30%) . In addition to the need to prescribe a statin of an appropriate intensity, sometimes there is a need to switch between statins because of intolerance. To facilitate the change from other statins to atorvastatin, the approximate equivalent effective daily doses are shown in Table 3. Of course, this change is only recommended in patients with a sustained statin treatment without any side effect.
HOW TO SWITCH TO A POLYPILL FOR CARDIOVASCULAR DISEASE PREVENTION IN PATIENTS WITH HYPERTENSION
When deciding to initiate treatment with the cardiovascular polypill in patients with hypertension and a history of a cardiovascular event (secondary prevention), different real-life clinical situations should be considered. This is because patients may variably differ for their hypertension grade and baseline LDL-cholesterol level, with a difference also in relative severity of these conditions. It is also because in treated patients, target BP and blood cholesterol levels may vary, the optimal target being unachieved for either condition or achieved for only one or both conditions, the last case having as a goal treatment simplification and continuing adherence. In each particular situation, the composition of the polypill (i.e. ramipril, atorvastatin and/or ramipril dose) must be adapted and, in circumstances where BP or LDL-cholesterol remain out of target, add other BP-lowering drugs, for example, CCBs or diuretics, or lipid-lowering drugs.
Figure 1 summarizes the steps to be followed in patients with a previous clinical cardiovascular event to switch from any baseline multiple pill treatment with ACEIs or ARBs and statins associated with specific medications for comorbidities (i.e. glucose-lowering drugs, diuretics, CCBs, antialdosterone drugs or betablockers for heart failure, post-myocardial infarction, etc.) to a polypill-based regimen in order to reduce the number of daily pills. Figure 2 shows an algorithm to guide clinicians to use the most appropriate polypill dosage based on the baseline BP (high-normal and hypertension grades 1–3). Following the recommendations of the 2018 ESC/ESH hypertension guidelines  a second antihypertensive drug (low dose of a diuretic or a CCB) has to be added to start treatment in patients with grade 2 or grade 3 hypertension; the algorithm also shows how to up-titrate the BP-lowering treatment when hypertension is still not at goal in spite of using the best possible polypill version. Also, lipid-lowering drugs, such as ezetimibe, and PCSK9i can be added in some cases, if tolerated, to achieve the target of LDL-cholesterol less than 70 mg/dl or less than 55 mg/dl if needed [48,50,53–55].
Finally, the 2019 guidelines on diabetes, pre-diabetes and CVD of the ESC in cooperation with the EASD , and the 2019 guidelines of the ACC/AHA on the primary prevention of CVD , both recommend the use of low-dose aspirin for primary prevention in middle-aged patients at high risk with advanced atherosclerotic CVD in whom AAS is well tolerated and no increased risk of bleeding is detected. For elderly patients, the decision may be individualized in those at no increased risk of bleeding . Figure 3 shows the steps that may be followed in these patients with multiple cardiovascular risk factors without clinical CVD, usually requiring many drugs/pills for treatment of these cardiovascular risk factors and comorbidities, when clinicians decide to indicate a low dose AAS. In order to reduce the number of pills, any baseline treatment may be switched to the polypill following the recommendations of equivalent effective doses of antihypertensive drugs (Tables 1 and 2) and statins (Table 3), and the algorithm showed in Fig. 2.
SUMMARY AND CONCLUSION
Pharmacological treatment recommended by guidelines for very high-risk patients with established CVD includes lipid-lowering drugs (statin alone or combined with ezetimibe/PCSK9i), antihypertensive agents (usually two or more) and antiplatelet therapy (low-dose aspirin). This baseline regimen has to be complemented with other drugs depending of the associated comorbidities, what may imply glucose-lowering drugs, loop diuretics, antialdosterone drugs and beta-blockers among others. Therefore, the number of pills to be taken by these patients is usually high, and adherence to these multiple pill therapeutic regimens and persistence on treatment is low, being the main factor for insufficient control of cardiovascular risk factors, with the consequence of an increased risk of recurrence of cardiovascular events and mortality. The CNIC polypill is the only polypill containing low-dose aspirin approved by the EMA and marketed in Europe and has been demonstrated to improve adherence. For this reason, guidelines recommended its use for secondary prevention of CVD. In addition, also European and American guidelines recommend the use of low-dose AAS for primary prevention of cardiovascular events in patients with multiple cardiovascular risk factors and advanced atherosclerotic process at high risk of thrombosis and low risk of bleeding.
The CNIC polypill containing a statin (atorvastatin), and ACEI (ramipril) and aspirin may be used in any patient for secondary and primary prevention of CVD tolerating all their components with the aim of reducing the number of pills, what in the clinical practice implies switching from the baseline treatment with an ACEIs or ARBs (alone or combined with diuretics or CCBs) and a statin (alone or associated with ezetimibe or a PCSK9i) to the components of the polypill (ramipril at different doses and atorvastatin at different doses). This article pretends to simplify the steps that clinicians may follow to switch from any baseline regimen to the polypill with the use of several algorithms and tables showing the equivalent effective daily doses of different ACEIs, ARBs and statins with ramipril and atorvastatin to facilitate switching, as well as the steps to be followed depending of the initial levels of BP and LDL-cholesterol values to achieve BP and lipid control with the association to the polypill of other BP-lowering or lipid-lowering drugs whenever needed.
Conflicts of interest
A.C. has received honoraria for lectures in symposia and educational activities sponsored by unrestricted grants from Abbott, Berlin-Chemie, Biolab, Boehringer, Ferrer, Menarini, Merck and Sanofi. R.K. has received honoraria for lectures in symposia and educational activities sponsored by unrestricted grants from Bayer, Berlin-Chemie, Daiichi-Sankyo, Ferrer, Menarini, Sanofi and Servier. A.J.M. has received honoraria for lectures in symposia and educational activities sponsored by unrestricted grants from Amgen, Berlin-Chemie, Ferrer, Menarini, Sanofi-Aventis and Servier. G.M. has received honoraria for lectures in symposia and educational activities sponsored by unrestricted grants from Daiichi-Sankyo, Ferrer, Medtronic, Menarini, Merck, Novartis, Recordati, Sanofi and Servier.
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