Hypertension and Cardiovascular Risk

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The lower level to which blood pressure should be taken and how soon treatment should be started are key considerations where aging and cardiovascular mortality risks are concerned. It has long been taught that blood pressure should be allowed to rise to a level deemed pre-hypertensive or hypertensive before non-pharmacological and pharmacological therapy is embarked upon. 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 at which epidemiological data are evaluated, only a continuous relationship between blood pressure and cardiovascular events. As such, the real strategy may be primary prevention.
The optimum level of blood pressure remains open to debate. Epidemiological evidence suggests that blood pressure below 120mmHg is least likely to be associated with cardiovascular events.1 Whether treatment of patients with blood pressure above this level results in the same cardiovascular risk reduction, and at what cost, must be addressed, along with whether there is 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 more appropriate would be the identification of the optimal therapeutic index of a given therapy and blood-pressure goal for each patient.
Bearing this in mind, this article will focus on three basic issues:

  • which blood-pressure determinations should be treated;
  • whether the 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 devices, as well as more sophisticated techniques using 24-hour ambulatory blood pressure monitoring (ABPM) 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 moving away from 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? ABPM technology has assisted in answering the question of whether there are clear variations in blood pressure throughout the day depending on activity, posture, stress, and, of course, sleep–wake patterns. Using this technology, morning elevations in blood pressure upon rising have now been linked to an increased risk for cardiovascular events.2,3 These important observations may change the way in which we approach antihypertensive therapy in selected patients. In addition, the predictive value of morning blood-pressure surge or loss of diurnal variation may 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 has not been widely adopted in clinical practice despite its sophistication, predictive value, and the fact that the cost of the determination has been reduced substantially and is often covered by insurance.
For years it has been appreciated that when patients undergo stress tests for evaluating cardiac ischemia, some experience dramatic increases in blood pressure 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 centered on the definition of pre-hypertension. The range of blood pressures between 120/80 and 140/90mmHg is likely to remain a battleground of discussion for the next few years. Although epidemiological data clearly indicate increasing risk of cardiovascular events with blood pressures in this range, much remains unknown about the safety and efficacy of lowering blood pressures depending on the patient’s 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 of incorporating these safely 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, fruit, 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 which 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-hypertensive (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 once daily), the incidence of hypertension at the two-year visit was 13.6% compared with 40.4% in the placebo group (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 suggest 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 of cessation of all medication, the overall differences in crossing the threshold of a systolic of 140 or a diastolic of 90mmHg 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 pharmacological treatment strategies is concerning because there have been no new substantial developments in the understanding of mechanism-based therapy. Consequently, practitioners are left using medication in more cases and higher doses than they think will work in a given patient. New therapeutic classes are being developed, including vasopeptidase inhibitors (VPIs) and renin inhibitors. Unfortunately, VPIs have been associated with a concerning risk for angioedema, which 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 are 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 hypertrophic cardiomyopathy. The thiazide diuretic has stood the test of time in multiple clinical trials, demonstrating its utility not only as a single agent, but also as part of an effective treatment regimen to reduce blood pressure and reduce the risk of cardiovascular events.9

However, 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 a consistent advantage when used in the full therapeutic dose for lowering blood pressure as part of an effective blood-pressure lowering multidrug regimen compared with other regimens.11 Renin–angiotensin blockers may also be helpful for some surrogate measures, such as 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 for use in blood-pressure reduction with an ACE inhibitor or an ARB. The real issue is tailoring the approach.

More often than not, healthcare providers focus on the best first-line therapy. In today’s 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, those with 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, such as 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 fixed-dose combinations to high fixed-dose combinations.

This pill-consolidation strategy may be the wave of the future that will allow healthcare providers to 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 concerns regarding how healthcare providers incorporate them into the practice. Should single drugs first be titrated and then switched 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 patient’s current blood pressure and his or her goal blood pressure. The JNC 7 guidelines suggest that if a patient is more than 20mmHg 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.
Future developments in antihypertensive 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 also, perhaps, how to best treat them. The cornerstone of all treatment should be improved lifestyle, although this may be difficult in many patients. Ongoing trials such as 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 1). 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-hypertension or hypertension much to ponder as we evaluate our own cardiovascular risk factors as we age. 

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