'Hypertension' and Cardiovascular Risk

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How low should blood pressure be taken and how soon should treatment be started are key questions in aging and considering cardiovascular mortality risks. But it might be important to ask whether 'hypertensionÔÇÖ is the right word. It has long been taught that one should allow blood pressure to rise to a level deemed 'pre-hypertensiveÔÇÖ or 'hypertensiveÔÇÖ before embarking on non-pharmacologic and pharmacologic therapy. Is this really the right tack in clinical medicine? A more appropriate consideration might be whether or not we should prevent the development of blood pressure elevation through earlier behavioral modification and even pharmacotherapy in some patients. There is no threshold as one looks at epidemiological data; only a continuous relationship between blood pressure and cardiovascular events. As such, the real strategy may be primary prevention.

What the right blood pressure is remains open to question. Epidemiologic evidence would suggest that blood pressures below 120mmHg are least likely to be associated with cardiovascular events,1 whether treatment of patients with higher blood pressures to these levels results in the same cardiovascular risk reduction, and at what cost, must be addressed, along with whether there a trade-off with regard to safety. Only newer clinical trials will be able to answer this question, as this may require more extensive involvement of various pharmacotherapies with their attendant cost and associated risk. Perhaps a more germane issue would be identifying the optimal therapeutic index of a given therapy and blood pressure goal for each patient.

With this background, this article will focus on three basic issues:

  • which blood pressure determinations should be treated;
  • whether ability to provide appropriate behavioral modification recommendations to assist in blood pressure control has been fully optimized; and
  • major future developments in antihypertensive therapy.

The debate about which blood pressures should be treated has been stimulated by newer technologies that now allow patients to monitor blood pressure at home with a multitude of different devices, as well as more sophisticated techniques using 24-hour ambulatory blood pressure measurement to evaluate the influence of diurnal variations in blood pressure as well as the effects of relaxation, exercise, and stress.

Office-based determinations have been the standard for nearly half a century. These measurements have been used to predict cardiovascular risk as well as response to treatment. Before leaving this standard we should be certain that other available determinations provide the same reliability and predictability. More studies are currently under way to evaluate the impact of home readings on the predictability of cardiovascular events. Most studies and anecdotal experience indicate that home readings tend to be lower than office-based readings. Does this provide anything more than the typical dynamic range of blood pressure when compared with office readings? Ambulatory blood pressure monitoring (ABPM) technology has assisted in answering this question: there are clear variations in blood pressure throughout the day, which depend on activity, posture, stress and, of course, sleep-wake patterns. Morning elevations in blood pressure upon rising have now been clearly tied to an increased risk for cardiovascular events using this technology.2,3 These important observations may change the way we approach antihypertensive therapy in selected patients. In addition, the predictive value of morning blood pressure surge or loss of diurnal variation may also assist in future planning of pharmacotherapy and even the type of pharmacotherapy, as some therapies may be more effective in blunting the morning surge or restoring the nocturnal dip. Ultimately, this strategy may prove to be important in reducing the incidence of cardiovascular events. However, ABPM technology, despite its sophistication and predictive value, has not been widely adopted in clinical practice despite the fact that the cost of the determination has been reduced substantially and is often covered by insurance.

In this regard, it has also been well appreciated for years that when patients undergo stress tests for evaluating cardiac ischemia, there are dramatic increases in blood pressure in some patients compared with others. How normal this response is, and whether there is a certain blood pressure level beyond which the response is abnormal, and ultimately predictive of cardiovascular events, is not known. Healthcare providers tend to overlook stress- or exercise-induced changes in blood pressure. There may be thresholds for concern and, even more importantly, specific therapeutic strategies that may not only prevent blunting of exercise-induced blood pressure increases, but also reduce the likelihood of associated events. These observations may also affect how antihypertensive care is tailored to individual patients.

With the advent of the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7),4 much discussion has been placed on the definition of 'pre-hypertensionÔÇÖ. The range of blood pressures between 120/80mmHg and 140/90mmHg will likely remain a battleground of discussion for the next few years. Although epidemiologic data clearly indicate increasing risk of cardiovascular events with blood pressures in this range, much remains to be known about the safety and efficacy of lowering blood pressures in this range depending on the patientÔÇÖs age, gender, ethnicity, comorbid medical problems, etc. It would be fair to state that the pre-hypertensive range should encourage healthcare providers to admonish patients about healthier lifestyles. With the increasing problems of obesity, sedentary lifestyle, and poor dietary habits, behavioral modification efforts have largely been ignored. However, the optimal way to safely incorporate these into treatment regimens on a large scale has not been fully established. Perhaps overlooked, and most important of all, would be an effort to reduce dietary salt consumption and increase intake of vegetables, fruits, etc. given the dramatic success of the Dietary Approaches to Stop Hypertension (DASH) diet studies.5,6 Hopefully, future studies will evaluate genetic susceptibility to salt-induced changes in blood pressure, as well as what behavioral and pharmacological interventions would be most appropriate.

The Trial of Preventing Hypertension (TROPHY) study is a provocative foray into a new field of cardiovascular therapeutics: the prevention of hypertension.7 Nearly 800 'pre-hypertensiveÔÇÖ (135/84mmHg) patients were randomized to placebo or an angiotensin receptor blocker (ARB) to evaluate likelihood of progression to 140/90mmHg. In the active treatment group (candesartan 16mg/qd) the incidence of hypertension at the two-year visit was 13.6% compared with the placebo group of 40.4% (p<0.001). Candesartan patients were switched to placebo after two years.At the four-year visit, with both groups receiving placebo, the hypertension incidence was 53.2% in the candesartan group and 63% in the placebo group. The relative risk reduction was 16% (p=0.007). There were no major differences in the incidence of adverse events between active treatment and placebo.

The results of this study suggests that patients in their late 40s who are overweight with modest cardiovascular risk factors may benefit from active therapy in preventing progression of blood pressure elevation. This effect is most evident with active therapy, and remains evident even after cessation of therapy for up to two years.

Although the absolute changes in blood pressure do tend to narrow between the placebo group and the active treatment group after two years off all medication, the overall differences in crossing the threshold of a systolic of 140 or a diastolic of 90 mmHg remain statistically significant and impressive. Although this study does not provide a cost effective analysis to address the issue of how many cardiovascular events can be prevented at what cost with this type of therapeutic approach, it does suggest that this type of prospective clinical trial should be performed. One has to wonder whether this approach would prevent patients from requiring three to four drug regimens for blood pressure later in life.

The future for established pharmacologic treatment strategies is concerning because there have been no new substantial understandings about mechanism-based therapy. Consequently, practitioners are left using medications in larger numbers and higher doses that they think will work in a given patient. New therapeutic classes are being developed, including the vasopeptidase inhibitors (VPI) and the renin inhibitors. Unfortunately the VPI have been associated with a concerning risk for angioedema that has limited the expansion of their use for clinical practice. Older agents, such as spironolactone, an aldosterone receptor antagonist, have been surpassed by new congeners that are better tolerated, such as eplerenone. Newer trials in congestive heart failure (CHF) demonstrate the advantage of aldosterone blockade in addition to renin-angiotensin system (RAS) inhibition to reduce cardiovascular events.8 However, data is lacking on the advantage of this approach in preventing primary and secondary cardiovascular events in patients with hypertension. Beta-blockers clearly have an established place in cardiovascular medicine, specifically in patients with angina, post-myocardial infarction (MI), systolic heart failure and hypertropic cardiomyopathy. The thiazide diuretic has stood the test of time in multiple clinical trials, demonstrating its utility not only as a single agent but as part of an effective treatment regimen to reduce blood pressure and reduce the risk of cardiovascular events.9 But some beta-blockers and diuretics may have adverse metabolic consequences that could prove to be of clinical significance. The calcium antagonist remains important in most regimens since it is capable of facilitating robust blood pressure reduction regardless of age, gender, ethnicity, salt intake, and non-steroidal anti-inflammatory drug (NSAID) use.10

However, in most well-executed clinical trials looking at the specific advantages of either cardio- or renal protection, the angiotensin-converting enzyme (ACE) inhibitors and the angiotensin II receptor blockers (ARBs) have demonstrated consistent advantage when used in the full therapeutic dose for lowering blood pressure, as part of an effective blood pressure lowering multi-drug regimen compared with other regimens (see Table 1).11 Renin angiotensin blockers may also be helpful for some surrogate measures like preventing new diabetes, decreasing microalbuminuria and left ventricular hypertrophy (LVH), or preventing new CHF.12 The introduction of renin inhibitors may hold the promise of more complete suppression of RAS, and may be effective to use for blood pressure reduction with an ACE inhibitor or an ARB. The real question is tailoring the approach.

More often than not healthcare providers are caught in the trap of asking what is the best first-line therapy. In todayÔÇÖs treatment world, this misses the point. What should come first is the establishment of an appropriate blood pressure goal for an individual patient. The next question is how many drugs will be needed (usually one for each 10mmHg systolic blood pressure reduction) and which classes. During the past decade the change in focus to systolic blood pressure, the need for lower systolic blood pressure goals in many patients (diabetics, kidney disease, etc.), and poor dietary habits coupled with obesity have markedly hampered our ability to control blood pressure in a simple way. The vast majority of patients now need two to three medications to control their blood pressure, even before the discussion starts about other medical comorbidities including diabetes, dyslipidemia, degenerative joint disease, cardiovascular disease, etc.

It is interesting that drug development strategies for controlling blood pressure are coming full circle. Although new classes like renin inhibitors will ultimately have a place in treatment regimens, the real focus for drug development now is to provide more robust blood pressure reduction with established agents being reformulated into higher doses and fixed dose combinations. In the past 10 years, there has been an evolution from low-dose fixed-dose combinations to high-dose fixed-dose combinations. This pill consolidation strategy may be the wave of the future so that healthcare providers can reduce the amount of pharmacotherapy a patient requires to control blood pressure and other cardiovascular disease risks.

This will facilitate simplicity and compliance. The concern about individual drug toxicity is less of an issue now given the fact that most of the medications currently used have been on the market for 10 or more years. Consequently, physicians can easily recognize the individual problems of these established agents. The mission is to achieve appropriate goals with the fewest pills possible. Interestingly, this strategy may also provide a psychological advantage as patients often equate pill counts with gravity of illness.

The development of more robust fixed dose combination regimens may also raise concern for healthcare providers as to how to incorporate them into the practice. Should one titrate single drugs first and then switch to a fixed dose? Or should fixed-dose agents be used at the time of the initiation of therapy? The answer to this question may lie in the difference between a patientÔÇÖs current blood pressure and their goal blood pressure. The JNC 7 guidelines suggest that if a patient is more than 20 mmHg systolic from goal, it would be appropriate to consider starting two medications in the form of a fixed-dose combination.4 Certainly, studies have indicated that this is a safe strategy and, in fact,may result in better long-term control rates.13 More experience among practicing clinicians will be important in expanding this strategy.

In perspective, future developments in 'antihypertensiveÔÇÖ therapy will revolve around earlier management strategies, perhaps embarking on treatment before patients require multiple medications for achieving appropriate blood pressure goals. Also important will be strategies to identify the high-risk patients who need earlier intervention and how best to treat them. Perhaps newer techniques for evaluating diurnal variations of blood pressure, the effects of exercise and stress on blood pressure, and interesting relationships between home and office readings will prove to be helpful in predicting not only those who need earlier intervention but perhaps how to best treat them. The cornerstone of all treatment should revolve around improved lifestyle, although this may be difficult in many patients. On-going trials like Avoiding Cardiovascular events through Combination therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) and Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) will assist in answering questions about optimal regimens of medications for reducing cardiovascular events. Certainly, completed clinical trials demonstrate how best to dose drugs in clinical trials (particularly the ARBs11 (see Table 2). So, as much as we have learned, much remains to be discovered. This will certainly give all of us who have an interest in the treatment of 'pre-hypertensionÔÇÖ or 'hypertensionÔÇÖ much to ponder and consider as we evaluate our own cardiovascular risk factors as we age.

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