Blood pressure (BP) reduction is the most important means for preventing hypertension-induced morbidity and mortality. The majority of hypertensive patients require two or more agents to have their BP controlled [1,2]. For example, in the Anglo-Scandinavian Cardiac Outcomes Trial, approximately 90% of patients required two or more antihypertensive drugs in an attempt to lower BP to levels below 140 mmHg systolic and 90 mmHg diastolic . In the Hypertension Optimal Treatment study, patients needed on average 3.3 drugs to attain goal pressures . In high-risk patients with diabetes, renal dysfunction, or previous cardiovascular complications, the number of drugs needed was even higher . In line with these findings, currently more than half of hypertensive patients require at least two drugs to achieve the BP goals recommended today. Thus combination therapy is strongly recommended by the guidelines published by the European Societies of Hypertension and Cardiology (ESH/ESC)  and the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) . Moreover, the reappraisal document published in 2009 by the ESH  suggests that antihypertensive treatment can be initiated with combination therapy as an alternative to titrating, rotating, and sequentially combining BP-lowering drugs of different classes. Whereas the current literature supports the aforementioned suggestion, some of these assertions remain unproven.
In absence of studies designed to answer the question, some post-hoc analyses of morbidity and mortality trials can provide relevant information, despite the limitations that the post-hoc analyses have . In the current issue of the Journal two studies approached the question with data coming from the Felodipine Event Reduction (FEVER)  and Valsartan Antihypertensive Long-Term Use Evaluation (VALUE)  studies, two outcome studies with hypertensive patients at different levels of cardiovascular risk. Both trials have included uncontrolled hypertensive patients, although they differed in inclusion criteria, study design, and classes of antihypertensive drugs investigated. Post-hoc analyses of both studies separately tried to answer relevant questions such as the following: (a) Is add-on therapy more effective than non-add-on therapy in the prevention of hypertension-induced cardiovascular complications? (b) Does cardiovascular risk differ between hypertensive patients whose BPs can be controlled without add-on therapy and those in whom BP control requires add-on therapy?
There was a general agreement in the responses to each of these questions provided by both studies. Hypertensive patients whose BPs could be controlled without add-on therapy had significantly fewer cardiovascular outcomes than patients who required add-on therapy to achieve control despite that the BP values were similar (though not identical) in both the groups of patients. Thus, patients responding less well to randomized treatment and requiring add-on therapy remained at a higher risk of all outcomes during the trial. Higher cardiovascular risk in those needing add-on therapy persisted despite several adjustments by baseline characteristics with potential impact (age, baseline BPs, previous cardiovascular events, diabetes), as well as by BPs achieved during the treatment periods. Likewise, when no add-on and add-on treatment study patients were matched by BPs (at baseline in VALUE or in-treatment in FEVER), results were still giving the same message. Consequently, it appears that adding antihypertensive drug to drug in the attempt to lower BP may not always be accompanied by further lowering of outcome incidence.
Two other studies have analysed the potential impact of the add-on therapy on cardiovascular endpoints. Whereas the Study on COgnition and Prognosis in the Elderly  trial provides information in the same direction as the above two studies commented, a post-hoc analysis of the Systolic Hypertension in Europe Trial  study reported a significant reduction in overall mortality in the add-on therapy group, with similar trends for fatal combined with nonfatal stroke and all cardiovascular events in patients with isolated systolic hypertension. The adjusted hazard ratios for cardiovascular mortality, cardiac events, myocardial infarction, and heart failure did not approach significance despite a difference of 9 mmHg SBP between the nitrendipine and the nitrendipine-enalapril groups .
Possible explanations of the persistence of high cardiovascular risk in those ‘resistant’ to initial therapy despite the addition of other antihypertensive drugs include: differences in baseline and in-treatment BPs; differences in cardiovascular risk level at the time of inclusion; and compliance with lifestyle and drug treatments.
Both studies minimize the importance of initial and in-treatment BP values in the differences of cardiovascular outcomes observed between patients with or without add-on therapy. Although several adjustments per BP, as well as further analyses with BP-matched patients, were done confirming a higher incidence of outcomes in patients with add-on therapy, the role of BP differences in the incidence of cardiovascular risk cannot be disregarded. In VALUE, baseline SBP was significantly higher in the add-on therapy groups, the highest in the add-on therapy group whose BP remained uncontrolled, and differences of about 2.5 mmHg persisted during the study. In FEVER, the BP issue is more complex due to the study design. Initially all patients started treatment with 12.5 mg of hydroclorothiazide and after a few weeks they were randomized to either placebo or felodipine. The add-on therapy in front of lack of response to placebo or felodipine, on top of hydroclorothiazide, was an increment of diuretic dose or other kind of antihypertensive drug. As could be expected, at the time add-on was decided BP was 9/4 mmHg higher in patients requiring add-on therapy, and a difference of 2.4/1.1 mmHg was maintained throughout the follow-up. Considering the relationship between BP differences in the arms of trials and the reduction in cardiovascular events reported in the trialists’ meta-analysis , the albeit small differences in BPs between patients with and without add-on therapy might have had an impact particularly since stroke was the main cardiovascular endpoint in FEVER, a study performed in Chinese patients. Furthermore, a high SBP is an indirect marker of arterial stiffness in the large arteries, an important component of the hypertension-induced damage and consequent cardiovascular risk .
Apparently no relevant differences in cardiovascular risk factors and organ damage were observed between the groups of no add-on and add-on therapy in both trials, and despite this, FEVER patients with add-on therapy had three times more cardiovascular events than those who did not need add-on therapy. Organ damage, however, was assessed in a very limited way, by ECG and serum creatinine only. More refined stratification of risk with the use of detailed organ damage assessment could have helped to better predict the level of risk in both groups of patients in the two studies . The ability to respond successfully to an initial antihypertensive therapy may be a useful marker to identify those patients with a lower underlying vascular and renal damage, whereas in those needing add-on therapy, underlying lesions can limit the BP-lowering effect of the drugs and be responsible for a high cardiovascular risk. In these high-risk patients, risk reduction by BP-lowering may soon reach a ‘ceiling effect’. In a review published in this Journal, Zanchetti  calculated the incidence of major cardiovascular events achieved in trials with antihypertensive agents in low or high-risk patients, elderly, and diabetic patients. Only in patients with baseline low risk was the cardiovascular event rate reduced to values below 3–6% in 5 years. In all the other groups, cardiovascular events were reduced no lower than to 12–14% in 5 years, despite extensive use of concomitant therapies.
Whether the use of antihypertensive classes of drugs other than those to which patients were initially randomized or subsequently added could have resulted in a more successful risk reduction has been commented in the two studies. Different classes of drugs were used in the mentioned studies; thus it seems that the drug used is not a relevant reason to explain the lower protection in add-on therapy patients .
Lack of adherence to lifestyle measures may have contributed to the lack of response to the initial treatments and, consequently, to the failure to reduce cardiovascular risk. Low adherence to salt restriction, persistence of alcohol intake, and smoking can limit not only the BP-lowering effect of drugs but also the control of other cardiovascular risk factors .
Other components of the total cardiovascular risk should also be taken into account. No information about the use of statins and antiplatelet drugs in each of the patient groups was provided. In high-risk hypertensive patients, these drugs may importantly contribute to reduce the incidence of cardiovascular events [16,17].
Finally, another aspect of the studies is worth some comment. In VALUE the incidence of events was also compared between controlled and uncontrolled add-on therapy patients. Despite the marked differences in BP, the overall incidence of events was similar in the two groups. The incidence of specific events, however, clearly differed. Whereas the incidence of stroke – which is known to be strongly BP dependent – was lower in controlled patients as compared to the uncontrolled ones, incidence of myocardial infarction was significantly higher in the controlled than in the uncontrolled patients. This observation, if confirmed in other studies, adds more controversy to the issues of the safety of BP reduction, the J-curve phenomenon, and the role of patients’ conditions in order to individualize the BP goal . Excessive BP reduction in patients with underlying coronary artery disease may produce undesired effects. In the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial study , patients with a baseline SBP below 130 mmHg who had an event (myocardial infarction or cardiovascular death) during the trial had significantly different baseline characteristics from those who did not. Patients having an event had greater probability of prestudy vascular disease (coronary or peripheral artery disease), as well as of being older, being more likely to be on antidiabetic or antihypertensive treatment, and having more evidence of renal dysfunction. In contrast, there were only minimal differences between the two groups in either initial or achieved BPs. This points to high baseline risk rather than excessive BP reduction as a key determinant of the J-curve phenomenon. How to identify patients at higher risk of coronary heart disease is a key issue to be explored in further studies, following the lead of the findings of the two studies here commented.
In conclusion, the main message of these two studies is that the absence of an adequate response to initial antihypertensive treatment can emerge as a marker of high cardiovascular risk despite the absence of other cardiovascular risk factors and/or identified organ damage. This does not undermine the recommendation of initiating combination therapy in order to minimize hypertension-induced morbidity and mortality, but raises important questions as to whether the usual strategy of adding antihypertensive drug to drug is always capable of further reducing cardiovascular risk in patients not fully responsive to initial therapy. If it is not always successful, what is the best approach to reach success? Is it the use of statins mandatory in patients who require add-on therapy even in the absence of compelling indications? Obviously, post-hoc analyses of subgroups should be considered exploratory, and used not to take decisions but to help designing potential future studies. Only prospective studies can provide answers to these important issues of the management of hypertension.
Conflicts of interest
There are no conflicts of interest.
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