Blood pressure control in the United States remains less than optimal despite recognition of theimportance of blood pressure control in preventing cardiovascular morbidity and mortality and themany treatment options now available. The most recent data showed that about 34% of patients havetheir hypertension under control, far short of the Healthy People 2000 goal to achieve 50% control.The date for realization of that goal has now been reset to 2010.
Recently, a distinguished faculty were brought together to discuss the topic "Optimizing BloodPressure Control in Clinical Practice." The faculty included George L. Bakris, MD, professor,Departments of Preventive and Internal Medicine, vice chairman, Department of Preventive Medicine,Rush University Medical Center, and director, Rush Hypertension Clinical Research Center, Chicago;Björn Dahlöf, MD, PhD, professor of medicine, Göteborg University Department of Medicine, director,Clinical Trials Unit, Sahlgrenska University Hospital/Östra, and vice president, Scandinavian CRIAB, Göteborg, Sweden; Barry J. Materson, MD, professor of medicine at the University of MiamiSchool of Medicine in Florida, and Robert A. Phillips, MD, PhD, chairman, Department of Medicine,Lenox Hill Hospital, and professor of medicine, New York University.
Combination antihypertensive regimen: a rational option for initial therapy
To achieve adequate control of blood pressure(BP) in most patients, physicians must avoid"clinical inertia," which often means using combinationantihypertensive therapy as the initialapproach to treatment.
Most patients with hypertension do not reachtarget BP with monotherapy. In the Antihypertensiveand Lipid-Lowering Treatment to PreventHeart Attack Trial (ALLHAT), for example, anaverage of 2 antihypertensive agents per patientwas needed after 5 years of follow-up, and morethan 20% of patients required 3 or more drugsto achieve BP control (<140/90 mm Hg). Thenumber of drugs used per patient increasedsteadily over the course of the trial, so that by theend of the study, more than 60% of patientswere on 2 or more drugs.
Am J Kidney
N Engl J Med.
J Clin Hypertens.
Other studies have corroborated the ALLHATfindings, averaging as many as 4 drugs per patientto achieve target BP levels (Figure 1) (. 2000;36:646-661; 2001;345:851-860; 2002;4:393-404).
Seventh Report of the Joint National
Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure
The (JNC 7) provides a clear mandate for use of combinationtherapy in selected patients. Specifically,the report states that combination therapyshould be considered as the initial approach forany patient whose BP is more than 20/10 mm Hgabove goal (ie, <140/90 mm Hg or <130/80 mmHg for those with diabetes or kidney disease)(. 2003;289:2560-2572).
The authors of JNC 7 further state, "Failure totitrate or combine medications, despite knowingthe patient is not at goal BP, represents clinicalinertia and must be overcome." Treating patientswith hypertension to goal is not easy, said Barry J.Materson, MD, but it is feasible. In ALLHAT, forexample, 64% of patients achieved a systolic BPof <140 mm Hg (. 2003;290:2805-2816).
Use of fixed-combination antihypertensives canhelp increase the proportion of patients who doachieve target BP levels, said Dr Materson. Severalstudies have demonstrated that a fixed combinationprovides greater BP reduction than monotherapy.
Am J Hypertens.
The Systolic Evaluation of Lotrel Efficacy andComparative Therapies (SELECT) compared thecalcium channel blocker (CCB) amlodipine besylate,the angiotensin-converting enzyme (ACE)inhibitor benazepril HCl, and a fixed combinationof the 2 agents in 505 patients. The magnitudeof BP reduction with the combination agentwas almost double the reduction achieved withthe ACE inhibitor and substantially more thanthe reduction with amlodipine besylate alone(2004;17:183A).
Am J Hypertens.
In the Safety of Lotrel Versus Amlodipine in aComparative Efficacy (SOLACE) trial, the BPcontrol rate was almost 50% greater with thefixed combination compared with the CCB(74% vs 54%). In a subset of patients with baselinesystolic BP ≥180 mm Hg, the fixed combinationresulted in mean systolic BP of 138 mmHg, compared with 150 mm Hg with CCBmonotherapy (2004;17:495-501). "The higher the systolic BP, the greater thereduction you are going to get with these combinationdrugs," said Dr Materson.
SOLACE also demonstrated a significantlylower rate of peripheral edema with the fixedcombination compared with monotherapy, ashas also been shown in other clinical trials(Figure 2).
"Most patients are going to require 2 or moredrugs to reach goal BP," said Dr Materson. "Itisn't easy, but you've got to get away from thetemptation of clinical inertia." Fixed-combinationantihypertensive drugs achieve greater BPreductions than monotherapy. The combinationagents might also improve adherence and reducecosts compared with use of 2 individual drugs,he concluded.
Combination antihypertensive regimens to be compared in international trial
Uncontrolled hypertension remains the leadingattributable cause of mortality worldwide,emphasizing the need for more aggressivetreatment, particularly with therapies that canprevent end-organ damage, according to BjörnDahlöf, MD, PhD.
Using stroke as an example, Dr Dahlöf citeddata showing a doubling of risk associated withevery 20-mm Hg increase in systolic BP or 10mm Hg in diastolic BP in all age groups and withno evidence of a threshold in the range of usualsystolic BP >115 mm Hg or usual diastolicBP > 75 mm Hg (. 2002;360:1903-1913).
"I've taken stroke data because many of usfear stroke more than any other cardiovascular[CV] complication, but if you take total CVevents, the relationship would be the same," saidDr Dahlöf.
Clinical trial data also show that even modestdifferences in BP can dramatically decrease therisk of CV disease and events. In the HypertensionOptimal Treatment (HOT) trial, for instance,achieved diastolic BP ranged between 81and 85 mm Hg, but that modest difference wasassociated with a 50% reduction in CV morbidity(. 1998;351:1755-1762).
The recent International Verapamil-TrandolaprilStudy (INVEST) provided additional evidence thatthe benefits of BP lowering continue well belowthe normotensive range, with no emergence of aJ-shaped curve (. 2003;290:2805-2816).
The CV benefits of BP reduction have beenestablished in a multitude of trials, using a varietyof antihypertensive agents, said Dr Dahlöf.However, only a minority of treated patientsachieve adequate BP control.
BP reduction is the driving force that will leadto lower CV disease. The key to better control isearly and continued use of combination therapy,Dr Dahlöf said. Unfortunately, most clinicaltrials to date have emphasized monotherapy asthe initial treatment approach, resulting in littledata to guide the selection of antihypertensivecombinations.
ALLHAT provided some insights into thevalue of combination therapy, but much of thecurrently available information pertains to add-ontreatment, not specific antihypertensive combinations(. 2002;288:2981-2997).
"We should look at first-line combinationtherapy because that is where most patients willend up," Dr Dahlöf advised. "We need to knowwhat are the best combinations, but, unfortunately,no morbidity or mortality data on fixedcombinations really exist."
The Losartan Intervention for EndpointReduction in Hypertension (LIFE) trial providedsome evidence of the benefits of pairing anangiotensin receptor blocker and a diuretic(. 2002;359:995-1003). The LIFE trialdemonstrated the importance of limiting endorgandamage related to hypertension. The combinationof a CCB and an ACE inhibitor also iseffective in reducing BP and end-organ damage,as shown in clinical evaluations of fixed-combinationamlodipine besylate/benazepril HCl.
Left ventricular hypertrophy (LVH) hasemerged as a good marker of hypertensive endorgandamage and offers a measurable target fortherapy. Improvement in LVH cannot be inferredfrom reduction in BP. As evidence, Dr Dahlöfcited an Italian study showing that LVH mightpersist in a substantial fraction of patientsdespite treatment of hypertension (.2002;39:744-749).
A Lotrel Evaluation of Hypertensive Patientswith Arterial Stiffness and Left VentricularHypertrophy (ALERT) provided evidence thatfixed-combination therapy offers superior endorganprotection. ALERT showed greater regression of arterial stiffness and LVH with the fixedcombination of amlodipine besylate/benazeprilHCl than with higher doses of amlodipine besylateor benazepril HCl monotherapy (2002;15[pt 2]:166A).
Am J Hypertens.
Much-needed information about first-linecombination antihypertensive therapy shouldcome from the ongoing Avoiding CardiovascularEvents through Combination Therapy inPatients Living with Systolic Hypertension(ACCOMPLISH) trial. The study comparesfixed-dose amlodipine/benazepril with a benazeprilHCl/hydrochlorothiazide diuretic combinationin 12 600 high-risk patients with hypertension(Figure 3) (2003;16[pt2]:193A).
ACCOMPLISH is the first large-scale trial tocompare 2 different fixed combinations as first-linetherapy for hypertension. The primary endpoint of the trial is composite CV mortality andmorbidity.
"The need for combination therapy toachieve BP control has been clearly established,"Dr Dahlöf concluded. "Certain combinationsmight have benefits that go beyondBP control, and that will be evaluated inACCOMPLISH."
Renal impairment calls for aggressive control of blood pressure
Hypertensive patients with renal impairmentpose a greater-than-normal challenge to BPcontrol but have a greater-than-normal need forthat control.
Kidney impairment is one of the "compellingindications" for starting antihypertensive therapywith a drug combination, as stated in JNC 7(. 2003;289:2560-2572). The compellingindication comes with a lower target BP(<130/80 mm Hg) compared with patients withuncomplicated hypertension. The NationalKidney Foundation and other health organizationsalso recommend lower BP goals forpatients with kidney disease.
Data from clinical trials "are very consistentand are sending a message that we need to bevery aggressive [about BP lowering] in peoplewith kidney disease," said George L. Bakris,MD. Results from trials dating back to the mid-1990s clearly show that adequate BP controldramatically slows the decline in renal function,as compared with poorly controlled or uncontrolledBP.
Even seemingly minor reductions in BP canreap huge clinical and economic benefits forpatients with kidney disease. For a 50-year-oldpatient with a creatinine level of 2 mg/dL, areduction of 10 mm Hg in systolic BP cantranslate into an additional 4.5 years offdialysis and a savings of about $250,000, saidDr Bakris.
A fixed-combination agent might provide theadded BP reduction required to meet a goal inhypertensive patients with kidney disease or diabetes,another high-risk group that has lower BPgoals.
J Clin Hypertens.
In the Study of Hypertension and the Efficacyof Lotrel in Diabetes (SHIELD) trial, 214patients with diabetes and hypertension wererandomized to fixed-combination amlodipinebesylate/benazepril HCl or to monotherapy withenalapril. Hydrochlorothiazide could be addedafter 8 weeks if BP still was not at goal (<130/85mm Hg). After 12 weeks, about 80% of patientsin the fixed-combination group were at goal,compared with about 30% in the enalapril group(2003;5:201-210).
"One of the points of the SHIELD data is thatthere is a perception that you catch up [with BPcontrol] if you add a diuretic in the short term,but, in fact, you don't catch up," said Dr Bakris.
Am J Hypertens.
The Lotrel and Enalapril in African Americanswith Diabetes (LEAAD) trial randomized269 patients with hypertension and type 2 diabetesto treatment with either fixed-combinationamlodipine besylate/benazepril HCl or enalaprilfor 24 weeks. Hydrochlorothiazide could beadded after 8 weeks. Significantly more patientsachieved target BP (<130/80 mm Hg) at 24weeks with amlodipine besylate/benazepril HClthan with enalapril (Figure 4). Moreover, thefixed combination led to a net reduction in urinaryprotein excretion (UPE), whereas UPE increasedduring follow-up in the enalapril-treatedpatients (2004;17:180A).
Arch Intern Med.
An International Society for Hypertension inBlacks consensus statement recommends combinationantihypertensive therapy as the initialapproach for hypertensive black patients whoseBP is more than 15/10 mm Hg above target(2003;163:525-541).
Clinical trial experience affords ample reasonnot to delay aggressive treatment in high-riskpatients, Dr Bakris continued. Clinical events usuallybegin to occur after 3 to 6 months of follow-up,and, in most instances, differences in BP controlplay a role in the occurrence of events. In the verylarge clinical trials of BP control, a difference of aslittle as 3 or 4 mm Hg often results in disproportionatelylarge reductions in clinical event rates.
Combination therapy will continue to emergeas an appropriate first-line option for manypatients as more clinical trial data become available.Two trials will add to the database in thenear future. The Gauging MicroalbuminuriaReduction with Lotrel in Diabetic Patients withHypertension (GUARD) trial will provide resultsof a head-to-head comparison of 2 fixed-dosecombinations (ACE inhibitor/CCB vs ACEinhibitor/diuretic). The ongoing ACCOMPLISHtrial will evaluate the same 2 fixed combinationsin almost 13 000 patients with hypertension.
"In the 21st century, it's combination versuscombination," said Dr Bakris. "The days ofmonotherapy are a bit historical, at least for thehigh-risk patient."
Regression of LV mass shown to reduce risk of cardiovascular events
The use of antihypertensive agents that reduceLVH can lead to greater risk reduction thancan be achieved with BP lowering that is notaccompanied by LVH improvement.
Hypertension is a key influence on LVH, butnot all drugs used to treat hypertension have thesame effects on LVH. Appreciating that distinctioncan help clinicians choose appropriate medicationsfor their patients with hypertension.
"LVH is highly prognostic for CV events,"said Robert A. Phillips, MD, PhD. "It's causedby a complex array of hemodynamic factors,particularly BP, and nonhemodynamic factors inwhich the renin-angiotensin-aldosterone system[RAAS] plays a role," he explained.
"BP reduction is critical to regression of LVH,and blockade of the RAAS has been shown inmany studies to be beneficial in LV mass regression.When LV mass regression occurs, not onlyis there a reduction in CV events, but improvementin CV function."
N Engl J Med.
LV mass rises with BP in men and women, andthe risk of CV disease and events increases withLV mass (1990;322:1561-1566)(Figure 5). Treatment that induces LV massregression significantly reduces the incidence ofCV events (. 1998;97:48-54).
Am J Cardiol
Dr Phillips and colleagues examined possibleexplanations for the association between LVHand CV disease. They found that midwall fractionalshortening improved as LV mass and baselinerelative wall thickness decreased, indicatingimproved ventricular function (.2001;87:61-65).
"We think that LV mass regression is associatedwith improved survival because the ventricleis starting to function better, which has beenshown in other studies," he said.
Am J Hypertens
Numerous studies have documented the associationbetween systolic BP and LVH. In severalstudies, Dr Phillips and his colleagues have shownthat higher nighttime BP might identify patientswho have a particularly high risk for LVH(. 2000;355:725-726; .2004;17:274).
The studies of nighttime BP employed 24-hour ambulatory monitoring, prompting acaveat from Dr Phillips. "You really can't useclinic monitoring to choose drugs or make drugchanges with LVH in mind," he said. "Clinicmonitoring is really not very useful for that."
Investigation of the effects of antihypertensivedrugs on LVH have demonstrated that differentclasses and agents affect LVH to differingdegrees. For example, an ACE inhibitor and athiazide diuretic induced the most regression inLV mass in 1 study (. 1997;95:2007-2014). Another study showed that the ACEinhibitor reduced LV fibrosis but a diuretic didnot (. 2000;102:1388-1393). TheLIFE trial showed that an angiotensin receptorblocker is superior to a beta blocker for inducingregression of LV mass (. 2003;108:684-690).
Several studies of combination antihypertensivetherapy have demonstrated significant regressionof LVH. For example, the recent Effects ofEplerenone, Enalapril, and Eplerenone/Enalaprilin Patients with Essential Hypertension and LeftVentricular Hypertrophy (4E) trial compared thealdosterone antagonist eplerenone with the ACEinhibitor enalapril and with the combination ofthe 2 drugs. All 3 treatments lowered BP to a similardegree, and all 3 reduced LV mass over time.However, combination therapy induced significantlymore LV regression than did either of themonotherapies (. 2003;108:1831-1838).
Am J Hypertens
More recently, the ALERT trial comparedamlodipine besylate, benazepril HCl, and fixed-combinationamlodipine besylate/benazepril HCl.All 3 treatments significantly reduced BP and LVmass compared with baseline. However, the fixedcombination induced more change in LV massthan either monotherapy, and the differencebetween the combination and amlodipine was statisticallysignificant. In addition, the combinationdrug led to a significantly greater improvement inarterial compliance compared with amlodipine(. 2004;17:37-42).